Non-imidazole aryl alkylamines compounds as histamine h3 receptor antagonists, preparation and therapeutic uses

ABSTRACT

The present invention discloses novel substituted aryl alkylamine compounds of Formula (I) or pharmaceutically acceptable salts thereof which have selective histamine-H3 receptor antagonist activity as well as methods for preparing such compounds. In another embodiment, the invention discloses pharmaceutical compositions comprising such cyclic amines as well as methods of using them to treat obesity and other histamine H3 receptor-related diseases.

BACKGROUND OF THE INVENTION

[0001] The present invention relates to histamine H3 receptorantagonists, and as such are useful in the treatment of disordersresponsive to the inactivation of histamine H3 receptors, such asobesity, cognitive disorders, attention deficient disorders and thelike.

[0002] The histamine H3 receptor (H3R) is a presynaptic autoreceptor andheteroreceptor found in the peripheral and central nervous system andregulates the release of histamine and other neurotransmitters, such asserotonin and acetylcholine. The histamine H3 receptor is relativelyneuron specific and inhibits the release of a number of monamines,including histamine. Selective antagonism of the histamine H3 receptorraises brain histamine levels and inhibits such activities as foodconsumption while minimizing non-specific peripheral consequences.Antagonists of the histamine H3 receptor increase synthesis and releaseof cerebral histamine and other monoamines. By this mechanism, theyinduce a prolonged wakefulness, improved cognitive function, reductionin food intake and normalization of vestibular reflexes. Accordingly,the histamine H3 receptor is an important target for new therapeutics inAlzheimer disease, mood and attention adjustments, cognitivedeficiencies, obesity, dizziness, schizophrenia, epilepsy, sleepingdisorders, narcolepsy and motion sickness.

[0003] The majority of histamine H3 receptor antagonists to dateresemble histamine in possessing an imidazole ring generally substitutedin the 4(5) position (Ganellin et al., Ars Pharmaceutica, 1995, 36:3,455-468). A variety of patents and patent applications directed toantagonists and agonists having such structures include EP 197840, EP494010, WO 97/29092, WO 96/38141, and WO96/38142. Theseimidazole-containing compounds have the disadvantage of poor blood-brainbarrier penetration, interaction with cytochrome P-450 proteins, andhepatic and ocular toxicities.

[0004] Non-imidazole neuroactive compounds such as beta histamines(Arrang, Eur. J. Pharm. 1985, 111:72-84) demonstrated some histamine H3receptor activity but with poor potency. EP 978512 published Mar. 1,2000 discloses non-imidazole aryloxy alkylamines discloses histamine H3receptor antagonists but does not disclose the affinity, if any, ofthese antagonists for recently identified histamine receptor GPRv53,described below. EP 0982300A2 (pub. Mar. 1, 2000) disclosesnon-imidazole alkyamines as histamine HS receptor ligand which aresimilar to the subject invention by having a phenoxy core structurealthough the subject invention is unique in the dissimilar substitutionsat the ortho, meta or para positions of the central benzene ring, theexact substitutions of the non-oxygen benzene ring substituent, and insome cases the presence of a saturated, fused heterocyclic ring appendedto the central benzene core. Furthermore the compounds of this inventionare highly selective for the H3 receptor (vs. other histaminereceptors), and possess remarkable drug disposition properties(pharmacokinetics).

[0005] Histamine mediates its activity via four receptor subtypes, H1R,H2R, H3R and a newly identified receptor designated GPRv53 [(Oda T., etal., J. Biol. Chem. 275 (47): 36781-6 (2000)]. Although relativelyselective ligands have been developed for H1R, H2R and H3R, few specificligands have been developed that can distinguish H3R from GPRv53. GPRv53is a widely distributed receptor found at high levels in humanleukocytes. Activation or inhibition of this receptor could result inundesirable side effects when targeting antagonism of the H3R receptor.Furthermore, the identification of this new receptor has fundamentallychanged histamine biology and must be considered in the development ofhistamine H3 receptor antagonists.

[0006] Because of the unresolved deficiencies of the compounds describedabove, there is a continuing need for improved methods and compositionsto treat disorders associated with histamine H3 receptors.

[0007] The present invention provides compounds that are useful ashistamine H3 receptor antagonists. In another aspect, the presentinvention provides compounds that are useful as selective antagonists ofthe histamine H3 receptor but have little or no binding affinity ofGPRv53. In yet another aspect, the present invention providespharmaceutical compositions comprising antagonists of the histamine H3receptor.

[0008] In yet another aspect, the present invention provides compounds,pharmaceutical compositions, and methods useful in the treatment ofobesity, cognitive disorders, attention deficient disorders and otherdisorders associated with histamine H3 receptor.

SUMMARY OF THE INVENTION

[0009] The present invention is a compound structurally represented byFormula I

[0010] or pharmaceutically acceptable salts thereof wherein:

[0011] X is O, NR⁷ or S;

[0012] R¹ is hydrogen,

[0013] C₁-C₈ alkyl optionally substituted with 1 to 4 halogens,

[0014] (CHR⁵)_(n)—C₃-C₇ cycloalkyl,

[0015] (CHR⁵)_(n) aryl,

[0016] (CHR⁵)_(n) heteroaryl, or

[0017] (CHR⁵)_(n)—O(CHR⁵)_(n)-aryl;

[0018] R² is independently R¹, or

[0019] COR¹, or cyclized with the attached nitrogen atom at the R¹position to form a 4, 5, or 6 member carbon ring, wherein one of saidcarbons is optionally replaced by one of O, S, NR¹ or CO, or wherein thering formed by R¹ and R is optionally substituted one to two times withC₁-C₄ alkyl;

[0020] R³ is independently C₃-C₇ cycloalkylene, or C₁-C₄ alkyleneoptionally substituted;

[0021] R⁴ is hydrogen,

[0022] halogen,

[0023] C₁-C₄ alkyl,

[0024] (CHR⁵)_(n)—C₃-C₇ cycloalkyl,

[0025] (CHR⁵)_(n) aryl,

[0026] (CHR⁵)_(n) heteroaryl,

[0027] (CHR⁵)_(n)—O(CHR⁵)_(n)-aryl or

[0028] CO or

[0029] cyclized with R⁵ to from a cyclopropyl ring;

[0030] R⁵ is hydrogen, or

[0031] C₁-C₄ alkyl;

[0032] R⁶ is hydrogen,

[0033] halo or

[0034] cyclized with the attached carbon atom at the R⁵ position to forma 5 to 6 member carbon ring,

[0035] cyclized with the attached carbon atom at the R⁷ position to forma 5 to 6 member heterocyclic ring or

[0036] R⁷ is hydrogen,

[0037] C₁-C₈ alkyl optionally substituted with 1 to 4 halogens,

[0038] (CHR⁵)_(n)—C₃-C₇ cycloalkyl,

[0039] (CHR⁵)_(n) aryl,

[0040] (CHR⁵)_(n) heteroaryl,

[0041] (CHR⁵)_(n)—O(CHR⁵)_(n)-aryl,

[0042] SO₂R¹ or

[0043] Cyclized with attached carbon on R⁸ to from a 5, 6, or 7 memberedcarbon ring optionally substituted with R⁹, CF₃, or CN, optionally oneof the said carbons is replaced by N, NR¹, CO;

[0044] R⁸ is hydrogen,

[0045] a bond,

[0046] C₁-C₈ alkyl

[0047] —SO₂ R⁹,

[0048] —CO₂ R¹⁰,

[0049] —CO R⁹,

[0050] —CONH R¹⁰;

[0051] R⁹ is hydrogen,

[0052] halogen,

[0053] C₁-C₈ alkyl optionally substituted with 1 to 4 halogens,

[0054] C₃-C₇ cycloalkyl,

[0055] aryl,

[0056] CH₂ aryl,

[0057] heteroaryl,

[0058] heterocycle,

[0059] —O(CHR⁵)_(n)-aryl,

[0060] —COR¹,

[0061] —CONRL R²,

[0062] —SO₂R¹,

[0063] —OR¹,

[0064] —N(R¹)₂,

[0065] NR¹R²,

[0066] —CH₂NR¹, R²,

[0067] —CONR¹R²

[0068] —NHSO₂R¹,

[0069] —NO₂,

[0070] —CO₂R¹,

[0071] —SO₂N(R¹)₂,

[0072] —S(O)_(n)R¹,

[0073] —OCF₃,

[0074] —CH2SR⁵,

[0075] R¹⁰ is hydrogen,

[0076] halogen,

[0077] C₁-C₈ alkyl optionally substituted with 1 to 4 halogens,

[0078] C₃-C₇ cycloalkyl,

[0079] aryl,

[0080] CH₂ aryl,

[0081] heteroaryl,

[0082] heterocycle,

[0083] —COR¹,

[0084] —CONR¹ R²,

[0085] —SO₂R¹,

[0086] —N(R¹)₂,

[0087] NR¹R²,

[0088] —CH₂NR¹, R²,

[0089] —CONR¹R²

[0090] —CO₂R¹,

[0091] —SO₂N(R¹)₂,

[0092] —S(O)_(n)R¹,

[0093] —CH2SR⁵,

[0094] and n is 0-4.

[0095] In preferred embodiments of Formula I the core phenoxy ring is ano, m, or p-disubstituted benzene, more preferably a p-disubstitutedbenzene. In alternative embodiments R⁶ forms a bicyclic carbon ring atthe R⁵ position. Alternatively, R⁶ may form a bicyclic heterocyclic ringat the R⁷ position. Preferably, X is nitrogen, R⁴ and R⁵ areindependently H or CH₃, R1 and R2 are independently a C₁-C₈ alkyl and R9is a di-C₁ to C₂ alkyl-amino.

[0096] The present invention is a pharmaceutical composition whichcomprises a compound of Formula I and a pharmaceutically acceptablecarrier. Pharmaceutical formulations of Formula I can provide a methodof selectively increasing histamine levels in cells by contacting thecells with an antagonist of the histamine H3 receptor, the antagonistsbeing a compound of Formula I.

[0097] The present invention further provides an antagonist of Formula Iwhich is characterized by having little or no binding affinity for thehistamine receptor GPRv53. Thus, a pharmaceutical preparation of FormulaI can be useful in the treatment or prevention of obesity, cognitivedisorders, attention deficient disorders and the like, which comprisesadministering to a subject in need of such treatment or prevention aneffective amount of a compound of Formula I. In addition, apharmaceutical preparation of Formula I can be useful in the treatmentor prevention of a disorder or disease in which inhibition of thehistamine H3 receptor has a beneficial effect or the treatment orprevention of eating disorders which comprises administering to asubject in need of such treatment or prevention an effective amount of acompound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

[0098] Throughout the instant application, the following terms have theindicated meanings:

[0099] The term “GPRv53” means a recently identified novel histaminereceptor as described in Oda, et al., supra. Alternative names for thisreceptor are PORT3 or H4R.

[0100] The term “H3R” means to the histamine H3 receptor that inhibitsthe release of a number of monoamines, including histamine.

[0101] The term “H1R” means to the histamine H1 receptor subtype.

[0102] The term “H2R” means to the histamine H2 receptor subtype.

[0103] The term “selective H3R antagonists” is defined as the ability ofa compound of the present invention to block forskolin-stimulated cAMPproduction in response to agonist R(−)α methylhistamine.

[0104] “Alkylene” are a saturated hydrocarbyldiyl radical of straight orbranched configuration made up of from 1 to 4 carbon atoms. Includedwithin the scope of this term are methylene, 1,2-ethane-diyl,1,1-ethane-diyl, 1,3-propane diyl, 1,2-propane diyl, 1,3 butane-diyl,1,4-butane diyl, and the like.

[0105] “C₃-C₇ cycloalkylene” are a saturated hydrocarbyldiyl radical ofcyclic configuration, optionally branched, made up of from 3 to 7 carbonatoms. Included within the scope of this term are cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl, and the like.

[0106] “Alkyl” are one to four or one to eight carbon atoms such asmethyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomericforms thereof.

[0107] “Aryl” are six to twelve carbon atoms such as phenyl,alpha-naphthyl, beta-naphthyl, m-methylphenyl, p-trifluoromethylphenyland the like. The aryl groups can also be substituted with one to 3hydroxy, fluoro, chloro, or bromo groups.

[0108] “Cycloalkyl” are three to seven carbon atoms such as cyclopropyl,cyclobutyl, cyclopentyl and cyclohexyl.

[0109] “Heteroaryl” are six to twelve carbon atoms aryls, as describedabove, containing the heteroatoms nitrogen, sulfur or oxygen.Heteroaryls are pyridine, thiophene, furan, pyrimidine, 2-pyridyl,3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl,3-pyridazinyl, 4-pryidazinyl, 3-pyrazinyl, 2-quinolyl, 3-quinolyl,1-isoquinolyl, 3-isoquinolyl, 4-isoquinolyl, 2-quinazolinyl,4-quinazolinyl, 2-quinoxalinyl, 1-phthalazinyl, 2-imidazolyl,4-imidazolyl, 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, 3-pyrazolyl,4-pyrazolyl, 5-pyrazolyl, 2-oxazolyl, 4-oxazolyl, 5-oxazolyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-indolyl, 3-indolyl,3-indazolyl, 2-benzoxazolyl, 2-benzothiazolyl, 2-benzimidazolyl,2-benzofuranyl, 3-benzofuranyl, 2-furanyl, 3-furanyl, 2-thienyl,3-thienyl, 2-pyrrolyl, 3-pyrrolyl, 1,2,4-oxadiazol-3-yl,1,2,4-oxadiazol-5-yl, 1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl,1,2,4-triazol-3-yl, 1,2,4-triazol-5-yl, 1,2,3,4-tetrazol-5-yl,5-oxazolyl, 1-pyrrolyl, 1-pyrazolyl, 1,2,3-triazol-1-yl,1,2,4-triazol-1-yl, 1-tetrazolyl, 1-indolyl, 1-indazolyl, 2-isoindolyl,1-purinyl, 3-isothiazolyl, 4-isothiazolyl, 5-isothiazolyl.

[0110] “Heterocycle” are three to twelve carbon atom cyclic aliphaticrings, wherein one or more carbon atoms is replaced by a hetero-atomwhich is nitrogen, sulfur or oxygen.

[0111] “Halogen” or “halo” means fluoro, chloro, bromo and iodo.

[0112] “Composition” means a pharmaceutical composition and is intendedto encompass a pharmaceutical product comprising the activeingredient(s), Formula I, and the inert ingredient(s) that make up thecarrier. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing a compound of thepresent invention and a pharmaceutically acceptable carrier.

[0113] The term “unit dosage form” means physically discrete unitssuitable as unitary dosages for human subjects and other non-humananimals, each unit containing a predetermined quantity of activematerial calculated to produce the desired therapeutic effect, inassociation with a suitable pharmaceutical carrier.

[0114] The terms “treating” and “treat”, as used herein, include theirgenerally accepted meanings, i.e., preventing, prohibiting, restraining,alleviating, ameliorating, slowing, stopping, or reversing theprogression or severity of a pathological condition, described herein.

[0115] In one embodiment, the present invention provides compounds ofFormula I as described in detail above. Another embodiments are wherethe phenoxy core structure is an o, m, or p-disubstituted aryl. Anotherembodiment is a compound wherein R⁶ is cyclized with the attached carbonatom at R⁷ to form, including the fused benzene ring, a substitutedtetrahydroisoquinoline ring. Another embodiment is a compound wherein Xis nitrogen, and wherein R⁷ and R⁸ are cyclized to form, together withX, a pyrrolidine ring, and wherein R⁹ is —CH²—N-pyrrolidinyl.

[0116] A preferred moiety for X is independently O or N.

[0117] A preferred moiety for R⁹ is C₁-C₈ dialkylamino. A more preferredembodiment is where the dialkylamino is dimethylamino.

[0118] It will be understood that, as used herein, references to thecompounds of Formula I are meant to also include the pharmaceuticalsalts, its enantiomers and racemic mixtures thereof.

[0119] Because certain compounds of the invention contain a basic moiety(e.g., amino), the compound of Formula I can exist as a pharmaceuticalacid addition salt. Such salts include sulfate, pyrosulfate, bisulfate,sulfite, bisulfite, phosphate, mono-hydrogenphosphate,dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide,iodide, acetate, propionate, decanoate, caprylate, acrylate, formate,isobutyrate, heptanoate, propiolate, oxalate, malonate, succinate,suberate, sebacate, fumarate, maleate, 2-butyne-1,4 dioate,3-hexyne-2,5-dioate, benzoate, chlorobenzoate, hydroxybenzoate,methoxybenzoate, phthalate, xylenesulfonate, phenylacetate,phenylpropionate, phenylbutyrate, citrate, lactate, hippurate,beta-hydroxybutyrate, glycollate, maleate, tartrate, methanesulfonate,propanesulfonate, naphthalene-1-sulfonate, naphthalene-2-sulfonate,mandelate and the like salts.

[0120] As stated earlier, the invention includes tautomers, enantiomersand other stereoisomers of the compounds also. Thus, as one skilled inthe art knows, certain aryls may exist in tautomeric forms. Suchvariations are contemplated to be within the scope of the invention.

[0121] The compounds of Formula I may be prepared by several processeswell known in the art. The compounds of the present invention areprepared by standard alkylation or Mitsunobu chemistries and reductiveanimations known to one skilled in the art, or by the methods providedherein, supplemented by methods known in the art. Generally, thisreaction is conducted in an organic solvent such as, for example,halogenated hydrocarbons, toluene, acetonitrile and the like, preferablyin the absence of moisture, at temperatures in the range about 0-100°C., by bringing together the ingredients in contact in the solventmedium and stirring for about 10 minutes to about 48 hours at suchtemperatures.

[0122] The compounds of Formula I, when existing as a diastereomericmixture, may be separated into diastereomeric pairs of enantiomers by,for example, fractional crystallization from a suitable solvent, forexample methanol or ethyl acetate or a mixture thereof. The pair ofenantiomers thus obtained may be separated into individual stereoisomersby conventional means, for example by the use of an optically activeacid as a resolving agent. Alternatively, any enantiomer of a compoundof the formula may be obtained by stereospecific synthesis usingoptically pure starting materials or reagents of known configuration orthrough enantioselective synthesis.

[0123] The Examples shown in Table 1 below are being provided to furtherillustrate the present invention. They are for illustrative purposesonly; the scope of the invention is not to be considered limited in anyway thereby. The preparation of compounds of Formula I, are depicted inthe schemes and procedures below.

[0124] Preparation ofN-{1-[4-(3-Dimethylamino-propoxy)-phenyl-N′,N′-dimethyl-ethane-1,2-diamine

EXAMPLE 2

[0125] To a 100 mL round-bottom flask was placed NaH (60% dispersion,38.4 mg, 1.0 mmol) and anhydrous THF (10 mL, 0.1 M) under an atmosphereof nitrogen. Then, a DMF solution of p-hydroxyacetophenone (62 mg, 0.5mmol) was added at 0 C. After 15 minutes, a DMF solution of3-chloro-N,N-diethyl-N-proplyamine (150 mg, 1.0 mmol) was added, and thereaction was allowed to slowly reach room temperature over 3 hours. Thereaction was then quenched with water, diluted with ether and washedwith water (3×20 mL) and brine (2×20 mL). Concentration in vacuoafforded 114 mg (92%) of an off-white solid. LCMS indicated a purity of95% and hit the mass, 249.1. This material was then dissolved in ethanol(4 mL, 0.1M) and 1-N,N-dimethylamino-2-N-methylaminoethane (114 mg, 0.45mmol) was added. After 15 minutes at room temperature, NaCNBH₃ (56 mg,0.9 mmol) was added and the reaction was allowed to stir overnight atroom temperature. The reaction was then with water, diluted with etherand washed with water (3×20 mL) and brine (2×20 mL). Concentration invacuo afforded 134 mg (93%) of an orange oil. Column chromatography(9:1, CH₂Cl₂:MeOH) afforded an orange oil. LCMS indicated a purity of99% and hit the mass, 321.2.

[0126] 7-Hydroxy-3,4-dihydro-1-H-isoquinoline-2-carboxylic acidtert-butyl ester is prepared by the procedure described in Kucznierz,et.al., J. Med. Chem. 1998, 41, 4983-4994. MS(ES−) 248.1 (M−H)⁻.

EXAMPLE 228

[0127]7-(3-Piperidin-1-yl-propoxy-3,4-dihydro-1-H-isoquinoline-2-carboxylicacid tert-butyl ester;

[0128] Procedure A: A 100 mL dioxane solution of7-hydroxy-3,4-dihydro-1-H-isoquinoline-2-carboxylic acid tert-butylester (5.0 g, 20 mmol) is stirred under N₂ as Cs₂CO₃ (13.3 g, 43 mmol),KI (0.1 g, 0.6 mmol), then N-(3-chloropropyl)piperidine (3.9 g, 24 mmol)are added in succession. The reaction mixture is heated at 90° C. for 10hours, cooled, filtered, and concentrated to give the crude product.Purification by chromatography (SiO₂; 0-10% MeOH/CH₂Cl₂/1% NH₄OHgradient) gives the product as an amber oil (7.5 g, 100% yield).MS(ES+)375.3(M+H)⁺.

EXAMPLE 238

[0129] 7-(3-Piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride;

[0130] Procedure B: A 50 mL CH₂Cl₂ solution of7-(3-Piperidin-1-yl-propoxy-3,4-dihydro-1-H-isoquinoline-2-carboxylicacid tert-butyl ester (5.1 g, 13.8 mmol) is stirred under N₂ at 0-10° C.as 4N HCl/dioxane (11.5 mL, 46 mmol) is added dropwise. After theaddition is complete, reaction mixture is stirred at this temperaturefor 30-60 min, then allowed to warm to room temperature. A whiteprecipitate forms and dry MeOH is added until clear solution isobtained. Additional 4N HCl/dioxane (11.0 mL, 44 mmol) is addeddropwise. After the addition is complete, reaction mixture is stirred atroom temperature. Reaction is followed by TLC (SiO₂ plate,CH₃Cl/MeOH/NH₄OH; 25/5/1) until starting material consumed (4-5 h).Reaction mixture is concentrated, dissolved in dry MeOH, concentrated,triturated in Et₂O, filtered, and dried in vacuo to give the di-HCl salt(4.5 g, 94% yield) as a white solid. MS(ES+)275.3(M+H)⁺ free base.

EXAMPLE 245

[0131]2-Methyl-7-(3-Piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline: A10 mL THF suspension of LAH (150 mg,4 mmol) is stirred under N₂ at 0-10°C. as a 10 mL THF solution of7-(3-piperidin-1-yl-propoxy-3,4-dihydro-1-H-isoquinoline-2-carboxylicacid tert-butyl ester (200 mg, 0.53 mmol) is added dropwise. Reactionmixture is allowed to warm to room temperature, refluxed 90 minutes,cooled to 0-10° C., quenched with H₂O and 15% aqueous NaOH, filtered,and the filtrate concentrated to give crude product. Material ispurified by chromatography (SiO₂; 0-10% MeOH/CH₂Cl₂/1% NH₄OH gradient)to give the product (82 mg, 54% yld). MS(ES+)289.1(M+H)⁺.

EXAMPLE 271

[0132]2-Ethyl-7-(3-Piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride;

[0133] Procedure C: An 80 mL CH₂Cl₂/MeOH (9:1) solution of7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (658972)(2.95 g, 8.5 mmol) is stirred under N₂, theMP-CNBH₃ resin(15 g, 38 mmol) added, the acetaldehyde (5 mL, 89 mmol)added, the pH is adjusted to ˜4 with glacial AcOH and reaction mixturestirred at room temperature for 18-20 hours. The reaction mixture isfiltered and the resin beads washed twice alternately with MeOH, thenCH₂Cl₂. The filtrate is concentrated and the residue is purified bychromatography (SCX-MeOH wash, elute 2M NH₃/MeOH; then (SiO₂; 0-10%MeOH/CH₂Cl₂/1% NH₄OH gradient) to give the pure free base.

[0134] Procedure D: A 50 mL THF/MeOH (1:1) solution of the free base(1.52 g, 5 mmol) is stirred under N₂ at 0-10° C. as 1N HCl/Et₂O (11.5mL, 11.5 mmol) is added dropwise. After the addition is complete,reaction mixture is allowed to warm to room temperature, then reactionmixture is concentrated, dissolved in dry MeOH, concentrated, trituratedin Et₂O, filtered, and dried in vacuo to give the di-HCl salt (4.5 g,94% yld) as a white solid. MS(ES+)303.3(M+H)⁺ free base.

EXAMPLE 292 (di-HCL Salt) EXAMPLE 273 (Free Base)

[0135]2-Cyclohexylmethyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride:2-Cyclohexylmethyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolineis prepared from7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (6 g, 17 mmol), MP-CNBH₃ (30 g, 76.5 mmol), andcyclohexanecarboxaldehyde (12.4 mL, 102 mmol) via a proceduresubstantially analogous to Procedure C except that the SCX column is notused in purification. The di-HCl salt product (4.9 g, 65% yld) isisolated as a white solid via a procedure substantially analogous toProcedure D. MS(ES+)371.4(M+H)⁺ free base.

EXAMPLE 244

[0136]2-Isopropyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline:2-Isopropyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolineis prepared from7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (520 mg, 1.5 mmol), MP-CNBH₃ (3.2 g, 7.5 mmol), andacetone (1.1 mL, 15 mmol) via a procedure substantially analogous toProcedure C except that the SCX column is not used in purification. Theproduct (210 mg, 44% yld) is isolated as a clear oil.MS(ES+)317.2(M+H)⁺.

EXAMPLE 275

[0137]1-[7-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]-ethanone:A 5 mL CH₂Cl₂ solution of7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (175 mg, 0.5 mmol) and NEt₃ (0.25 mL, 1.7 mmol) isstirred under N₂, a 1 mL CH₂Cl₂ solution of acetyl chloride (0.043 mL,0.6 mmol) is added, and reaction is stirred at room temp. for 5-6 hours.Reaction mixture is quenched with MeOH, concentrated and the residue ispurified by chromatography (SCX-MeOH wash, elute 2M NH₃/MeOH; then(SiO₂; 0-10% MeOHlCH₂Cl₂/1% NH₄OH gradient) to give the product (90 mg,58% yld). MS(ES+)317.1(M+H)⁺

EXAMPLE 257

[0138][7-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]-thiophen-2-yl-methanone;

[0139] Procedure E: A 7 mL CHCl₃/t-BuOH/MeCN (5:1:1) mixture of7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (256 mg, 0.74 mmol), resin bound DCC (1.1 g, 0.9 mmol),hydroxybenzotriazole (HOBt, 150 mg, 1.1 mmol), andthiophene-2-carboxylic acid (118 mg, 0.9 mmol) is shaken in a cappedvial at room temperature for 48 hours. The reaction mixture is filteredand the resin beads washed twice alternately with MeOH, then CH₂Cl₂. Thefiltrate is concentrated and the residue is purified by chromatography(SCX-MeOH wash, elute 2M NH₃/MeOH; then SiO₂; 0-10% MeOH/CH₂Cl₂/1% NH₄OHgradient) to give the pure free base as a solid (180 mg, 63% yld).MS(ES+) 385.1(M+H)⁺. A 3 mL dry MeOH solution of the free base (45 mg,0.12 mmol) is stirred with 1N HCl/Et₂O (0.18 mL, 0.18 mmol) for 5minutes, concentrated, triturated with Et₂O, filtered, and dried invacuo to the HCl salt as an off-white solid (46 mg). MS(ES+) 385.1(M+H)⁺ free base.

EXAMPLE 274

[0140]2-Dimethylamino-1-[7-(3-piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]-ethanone:2-Dimethylamino-1-[7-(3-piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]-ethanoneis prepared from7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (175 mg, 0.5 mmol), PS-DCC (800 mg, 1.1 mmol), HOBt (80mg, 0.77 mmol), NEt₃ (0.21 mL, 1.5 mmol) and N,N-dimethylglycine (1.1mL, 15 mmol) via a procedure substantially analogous to Procedure Eexcept that PS-trisamine resin beads (700 mg, 2.6 mmol) is used in thework up to scavenge the excess HOBt and N,N-dimethylglycine. The freebase product (35 mg, 19% yld) is isolated as an oil. MS(ES+)360.5(M+H)⁺.

EXAMPLE 266

[0141]7-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid isopropylamide: A 10 mL CH₂Cl₂ solution of7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (254 mg, 0.73 mmol), NEt₃ (0.20 mL, 1.4 mmol), isopropylisocyanate (192 mg, 2.2 mmol), and 4-dimethylaminopyridine (12 mg, 0.1mmol) is stirred under N₂, at room temperature for 18 hours. Thereaction mixture is concentrated and the residue is purified bychromatography (SCX-MeOH wash, elute 2M NH3/MeOH; then SiO₂; 0-10%MeOH/CH₂Cl₂/1% NH₄OH gradient) to give pure product (110 mg, 42% yld).MS(ES+) 360.2(M+H)⁺.

EXAMPLE 249

[0142]2-Benzenesulfonyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline;

[0143] Procedure F: A 5 mL CH₂Cl₂ solution of7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (185 mg, 0.53 mmol) and NEt₃ (0.22 mL,1.8 mmol) isstirred under N₂, benzenesulfonyl chloride (0.08 mL, 0.62 mmol) isadded, and reaction is stirred at room temperature for 5-6 hours.Reaction mixture is diluted with EtOAc, washed with saturated aqueousNa₂CO₃, and the aqueous layer back-extracted with EtOAc. The EtOAcextracts are combined, dried (Na₂SO₄), and concentrated. The residue ispurified by chromatography (SiO₂; 0-6% MeOH/CH₂Cl₂/1% NH₄OH gradient) togive the product (160 mg, 73% yld). MS(ES+) 415.1(M+H)⁺.

EXAMPLE 268

[0144]7-(3-Piperidin-1-yl-propoxy)-2-(thiophene-2-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline:7-(3-Piperidin-1-yl-propoxy)-2-(thiophene-2-sulfonyl)-1,2,3,4-tetrahydro-isoquinolineis prepared from7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (175 mg, 0.5 mmol), NEt₃ (0.25 mL, 1.8 mmol), andthiophene-2-sulfonyl chloride (114 mg, 0.63 mmol) via a proceduresubstantially analogous to Procedure F except that an additional SCXcolumn purification step is performed to give the product (160 mg, 76%yld). MS(ES+)421.1(M+H)⁺.

EXAMPLE 267

[0145]7-(3-Piperidin-1-yl-propoxy)-2-(propane-2-sulfonyl)-1,2,3,4-tetrahydro-isoquinoline:7-(3-Piperidin-1-yl-propoxy)-2-(propane-2-sulfonyl)-1,2,3,4-tetrahydro-isoquinolineis prepared from7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (175 mg, 0.5 mmol), NEt₃ (0.25 mL, 1.8 mmol), andisopropylsulfonyl chloride (0.07 mL, 0.60 mmol) via a proceduresubstantially analogous to Procedure F except that an additional SCXcolumn purification step is performed to give the product (93 mg, 49%yld). MS(ES+) 381.1(M+H)⁺.

EXAMPLE 284

[0146]2-Methanesulfonyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinehydrochloride:2-Methanesulfonyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinehydrochloride is prepared from7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (183 mg, 0.52 mmol), NEt₃ (0.25 mL, 1.8 mmol), andmethanelsulfonyl chloride (0.05 mL, 0.66 mmol) via a proceduresubstantially analogous to Procedure F except that an additional SCXcolumn purification step is performed to give the free base product. A 5mL dry MeOH solution of the free base (110 mg, 0.31 mmol) is stirredwith 1N HCl/Et₂O (0.50 mL, 0.5 mmol) for 5 minutes, concentrated,triturated with Et₂O, the Et₂O decanted, and the residue dried in vacuoto give the HCl salt as a glass (118 mg, 65% yld). MS(ES+) 353.2(M+H)⁺free base.

EXAMPLE 286

[0147]2-(4-Methoxy-benzenesulfonyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinehydrochloride:2-(4-Methoxy-benzenesulfonyl-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinehydrochloride is prepared from7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (150 mg, 0.43 mmol), NEt₃ (0.21 mL, 1.5 mmol), and4-methoxybenzenesulfonyl chloride (115 mg, 0.57 mmol) via a proceduresubstantially analogous to Procedure F except that an additional SCXcolumn purification step is performed to give the free base product. A 5mL dry MeOH solution of the free base (131 mg, 0.29 mmol) is stirredwith 1N HCl/Et₂O (0.40 mL, 0.4 mmol) for 5 minutes, concentrated,triturated with Et₂O, filtered, and dried in vacuo to give the HCl salt(118 mg, 57% yld). MS(ES+) 445.2(M+H)⁺ free base.

EXAMPLE 277

[0148]1-{4-[7-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinoline-2-sulfonyl]-phenyl}-1-{4-[7-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinoline-2-sulfonyl]-phenyl}-ethanoneis prepared from7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (175 mg, 0.5 mmol), NEt₃ (0.25 mL, 1.8 mmol), and4-acetylbenzenelsulfonyl chloride (131 mg, 0.60 mmol) via a proceduresubstantially analogous to Procedure F except that an additional SCXcolumn purification step is performed to give the product (85 mg, 37%yld). MS(ES+) 457.1(M+H)⁺.

EXAMPLE 276

[0149] 2-(4-n-Butyl-benzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline:2-(4-n-Butyl-benzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolineis prepared from7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (175 mg, 0.5 mmol), NEt₃ (0.25 mL, 1.8 mmol), and4-(n-butyl)benzenesulfonyl chloride (140 mg, 0.60 mmol) via a proceduresubstantially analogous to Procedure F except that an additional SCXcolumn purification step is performed to give the product (165 mg, 70%yld). MS(ES+)471.1(M+H)⁺.

EXAMPLE 278

[0150]2-(4-Cyanobenzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline:2-(4-Cyanobenzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolineis prepared from7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (175 mg, 0.5 mmol), NEt₃ (0.25 mL, 1.8 mmol), and4-cyanobenzenesulfonyl chloride (121 mg, 0.60 mmol) via a proceduresubstantially analogous to Procedure F except that an additional SCXcolumn purification step is performed to give the product (157 mg, 71%yld). MS(ES+) 440.1(M+H)⁺.

EXAMPLE 287

[0151]4-[7-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinoline-2-sulfonyl]-benzamide:A 1.4 mL DMSO mixture of K₂CO₃ is stirred under N₂,2-(4-cyanobenzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline(75 mg, 0.17 mmol) is added, 0.2 mL H₂O added, followed by 30% H₂O₂ (1.4mL, 12 mmol) and reaction is stirred at room temperature for 4 hours.The reaction mixture is diluted with MeOH, filtered, and the solidswashed twice with MeOH. The filtrate is concentrated and the residue ispurified by chromatography (SCX-MeOH wash, elute 2M NH₃/MeOH; then SiO₂;0-10% MeOH/CH₂Cl₂/1% NH₄OH gradient) to give the product as an off-whitesolid (26 mg, 26% yld). MS (ES+)458.2(M+H)⁺.

EXAMPLE 285

[0152]2-(4-Fluoro-benzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinehydrochloride:2-(4-Fluoro-benzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinehydrochloride is prepared from7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (158 mg, 0.45 mmol), NEt₃ (0.21 mL, 1.5 mmol), and4-fluorobenzenesulfonyl chloride (115 mg, 0.55 mmol) via a proceduresubstantially analogous to Procedure F except that an additional SCXcolumn purification step is performed to give 140 mg of free baseproduct. The free base is converted to the HCl salt (150 mg, 71% yld)via a procedure substantially analogous Procedure D. MS (ES+)433.2(M+H)⁺free base.

EXAMPLE 304

[0153]2-(2-Fluoro-benzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline:2-(2-Fluoro-benzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolineis prepared from7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (104 mg, 0.3 mmol), NEt₃ (0.14 mL, 1.1 mmol), and2-fluorobenzenesulfonyl chloride (80 mg, 0.41 mmol) via a proceduresubstantially analogous to Procedure F except that an additional SCXcolumn purification step is performed to give the free base product (85mg, 66% yld) as an amber oil. MS (ES+) 433.2(M+H)⁺.

EXAMPLE 305

[0154]2-(3-Fluoro-benzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline:2-(3-Fluoro-benzenesulfonyl)-7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolineis prepared from7-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (104 mg, 0.3 mmol), NEt₃ (0.14 mL, 1.1 mmol), and3-fluorobenzenesulfonyl chloride (80 mg, 0.41 mmol) via a proceduresubstantially analogous to Procedure F except that an additional SCXcolumn purification step is performed to give the free base product (90mg, 70% yld) as an off-white solid. MS (ES+) 433.2(M+H)⁺.

[0155] 6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester is prepared by the procedures similar to thosedescribed in Selnick, H. G.; Smith, G. R.; Tebben, A. J.; Synth.Commun.1995, 25, 3255-3262.

EXAMPLE 127

[0156]6-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester: To a round-bottom flask, equipped with stir barand septum, is placed 6-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (1 g, 4.01 mmol), KI (599 mg, 4.01 mmol) and NaH(162 mg, 95% dry, 6.42 mmol). Then, dry DMF (20 mL, 0.5 M) is added viasyringe followed by N-(3-chloropropyl)piperidine (0.85 mL, 5.2 mmol).The reaction is allowed to stir at 70 degrees overnight. In the morning,the reaction is quenched with water, extracted into EtOAc (3×20 mL) anddried over brine. Column chromatography in 9:1 DCM:MeOH affords6-(3-piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester an orange oil (1 g, 67%). Mass sec hit M+1, 375;LCMS>95% @230 nm and ELSD.

[0157] In a similar manner the Examples 35, 139, and 164 are prepared:

EXAMPLE 35

[0158]6-(3-Dimethylamino-propoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester; M+1 335

EXAMPLE 139

[0159]6-[3-(2-Methyl-piperidin-1-yl)-propoxy]-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester; M+1 389

EXAMPLE 164

[0160]6-(2-Piperidin-1-yl-ethoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester; M+1 361.

EXAMPLE 128

[0161] 6-(3-Piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride: To a round-bottom flask, equipped with stir bar andseptum, is placed6-(3-piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (1 g, 2.6 mmol), DCM (20 mL) and 4M HCl/dioxane (5mL). The reaction is allowed to stir at room temperature for 3 h. Afterthis time, the reaction is concentrated, dissolved in MeOH andconcentrated again affording6-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride as a white solid (800 mg, 87%). Mass spec hit M+1, 275;LCMS>95% @ 230 nm and ELSD.

[0162] In a similar manner the Examples 40, 140, and 165 are prepared:

EXAMPLE 40

[0163]Dimethyl-[3-(1,2,3,4-tetrahydro-isoquinolin-6-yloxy)-propyl]-aminedihydrochloride; M+1 235.

EXAMPLE 140

[0164]6-[3-(2-Methyl-piperidin-1-yl)-propoxy]-1,2,3,4-tetrahydro-isoquinolinedihydrochloride; M+1 289.

EXAMPLE 165

[0165] 6-(2-Piperidin-1-yl-ethoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride; M+1 261.

EXAMPLE 129

[0166]2-Ethyl-6-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline: Toa 25 mL round-bottom flask is placed6-(3-Piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (700 mg, 2.01 mol), MP-CNBH₃ (2.5 g, 6.05 mmol, 2.42mmol/g) and DCM/MeOH (9 mL/1 mL). Then, acetaldehyde is added (0.7 mL,12 mmol) and the reaction is allowed to stir overnight. The reaction isthen filtered, washed with DCM/MeOH and concentrated. Columnchromatography in 9:1 DCM:MeOH affords2-ethyl-6-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline(493 mg, 71%) of a viscous oil. Mass spec hit M+1, 303; LCMS>95% @ 230nm and ELSD. Array synthesis followed this general procedure in 4 mLvials to make the following compounds: Example Name MS 76[3-(2-Ethyl-1,2,3,4-tetrahydro-isoquinolin-6-yloxy)-propyl]- 263dimethyl-amine 77{3-[6-(3-Dimethylamino-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]- 320propyl}-dimethyl-amine 802-[6-(3-Dimethylamino-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]- 292acetamide 81 Dimethyl-{3-[2-(2-piperidin-1-yl-ethyl)-1,2,3,4-tetrahydro-346 isoquinolin-6-yloxy]-propyl}-amine 82Dimethyl-[3-(2-pyridin-3-ylmethyl-1,2,3,4-tetrahydro-isoquinolin-6- 326yloxy)-propyl]-amine 83Dimethyl-[3-(2-pyridin-2-ylmethyl-1,2,3,4-tetrahydro-isoquinolin-6- 326yloxy)-propyl]-amine 1412-Ethyl-6-[3-(2-methyl-piperidin-1-yl)-propoxy]-1,2,3,4-tetrahydro- 317isoquinoline 1452-Cyclopropylmethyl-6-(3-piperidin-1-yl-propoxy)-1,2,3,4- 329tetrahydro-isoquinoline 1462-Cyclopentylmethyl-6-(3-piperidin-1-yl-propoxy)-1,2,3,4- 357tetrahydro-isoquinoline 1472-Cyclohexylmethyl-6-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro- 371isoquinoline 1482-(2-Ethyl-butyl)-6-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro- 359isoquinoline 1496-(3-Piperidin-1-yl-propoxy)-2-propyl-1,2,3,4-tetrahydro- 317isoquinoline 1662-Ethyl-6-(2-piperidin-1-yl-ethoxy)-1,2,3,4-tetrahydro-isoquinoline 289169 2-Cyclopropylmethyl-6-(2-piperidin-1-yl-ethoxy)-1,2,3,4-tetrahydro-315 isoquinoline 1702-Cyclopentylmethyl-6-(2-piperidin-1-yl-ethoxy)-1,2,3,4-tetrahydro- 343isoquinoline 1712-Cyclohexylmethyl-6-(2-piperidin-1-yl-ethoxy)-1,2,3,4-tetrahydro- 357isoquinoline 1722-(2-Ethyl-butyl)-6-(2-piperidin-1-yl-ethoxy)-1,2,3,4-tetrahydro- 345isoquinoline 1682-Isopropyl-6-(2-piperidin-1-yl-ethoxy)-1,2,3,4-tetrahydro- 303isoquinoline

[0167]

EXAMPLE 250

[0168]2-Ethyl-6-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride:2-Ethyl-6-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline(5.12 g, 16.9 mmol) is dissolved in MeOH (50 mL), and 1M HCl in ether isadded dropwise (37.2 mL, 37.2 mmol) and the mixture is stirred for 10minutes and concentrated to give the dihydrochloride salt as a whitesolid (6.0 g, 93%).

EXAMPLE 143

[0169]2-Isopropyl-6-[3-(2-methyl-piperidin-1-yl)-propoxy]-1,2,3,4-tetrahydro-isoquinoline:To a flask equipped with a stir bar is placed6-[3-(2-Methyl-piperidin-1-yl)-propoxy]-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (300 mg, 0.83 mmol), acetone (excess), NaCNBH₃ (155 mg,2.5 mmol) in MeOH (8 mL) and the mixture stirred at room temperature for2 h. The reaction mixture is diluted with water, and extracted withCH₂Cl₂. The organic phase is dried over Na₂SO₄ and concentrated. M+1331, LCMS >98% @ 230 nm and ELSD.

[0170] In a similar manner Example 138 is prepared:

EXAMPLE 138

[0171]2-Isopropyl-6-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline;M+1 317, LCMS 100% @ 230 nm and ELSD.

EXAMPLE 162

[0172][6-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]-thiazol-2-yl-methanone:To a 4 mL vial is placed6-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (28 mg, 0.08 mmol), resin-bound DCC (134 mg, 0.16 mmol,1.2 mmol/g), HOBt (16 mg, 0.12 mmol), pyrazole carboxylic acid (13 mg,0.1 mmol) and a 5:1:1 mixture of CHCl₃:CH₃CN:tBuOH. The vial is agitatedby means of a lab quake shaker overnight. In the morning, PS-trisamine(134 mg, 0.4 mmol, 3.0 mmol/g) is added and the reaction is againallowed to rotate overnight to scavenge excess carboxylic acid and HOBt.Filtration, washing with DCM/MeOH and concentration affords a orangefoam. Filtration through a short pipet column provides 24 mg (80%) of[6-(3-piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]-thiazol-2-yl-methanoneas an orange solid. Mass spec hit M+1, 386; LCMS>95% @ 230 nm and ELSD.Array synthesis follows this general procedure in 4 mL vials to make thefollowing examples: Example Name MS 78[6-(3-Dimethylamino-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]- 474(1-phenyl-5-trifluoromethyl-1H-pyrazol-4-yl)-methanone 1341-[6-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]-ethanone315 156 [6-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]-386 (tetrahydro-furan-2-yl)-methanone 157(5-Methyl-furan-2-yl)-[6-(3-piperidin-1-yl-propoxy)-3,4-dihydro- 3831H-isoquinolin-2-yl]-methanone 158[6-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]- 368(1H-pyrrol-2-yl)-methanone 1592-Methylsulfanyl-1-[6-(3-piperidin-1-yl-propoxy)-3,4-dihydro-1H- 363isoquinolin-2-yl]-ethanone 160[6-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]- 385thiophen-2-yl-methanone 161N,N-Dimethyl-4-oxo-4-[6-(3-piperidin-1-yl-propoxy)-3,4-dihydro- 4021H-isoquinolin-2-yl]-butyramide 162[6-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]- 386thiazol-2-yl-methanone 1635-[6-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinoline-2- 386carbonyl]-pyrrolidin-2-one 1752-Dimethylamino-1-[6-(3-piperidin-1-yl-propoxy)-3,4-dihydro-1H- 360isoquinolin-2-yl]-ethanone 176(1-Methyl-pyrrolidin-2-yl)-[6-(3-piperidin-1-yl-propoxy)-3,4- 386dihydro-1H-isoquinolin-2-yl]-methanone 1772-Dimethylamino-1-[6-(2-piperidin-1-yl-ethoxy)-3,4-dihydro-1H- 346isoquinolin-2-yl]-ethanone 1821-[6-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]- 332propan-1-one 183Cyclopropyl-[6-(3-piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]-344 methanone 184Cyclobutyl-[6-(3-piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]-358 methanone 185Cyclopentyl-[6-(3-piperidin-1-yl-propoxy)-3,4-dihydro-1H- 372isoquinolin-2-yl]-methanone 1862-Methyl-1-[6-(3-piperidin-1-yl-propoxy)-3,4-dihydro-1H- 346isoquinolin-2-yl]-propan-1-one 187Cyclohexyl-[6-(3-piperidin-1-yl-propoxy)-3,4-dihydro-1H- 385isoquinolin-2-yl]-methanone 1882-Ethyl-1-[6-(3-piperidin-1-yl-propoxy)-3,4-dihydro-1H- 373isoquinolin-2-yl]-butan-1-one 193[6-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]- 381pyridin-4-yl-methanone 194[6-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]- 381pyridin-3-yl-methanone 195[6-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]- 381pyridin-2-yl-methanone 196Isoxazol-5-yl-[6-(3-piperidin-1-yl-propoxy)-3,4-dihydro-1H- 371isoquinolin-2-yl]-methanone

[0173]

EXAMPLE 178

[0174]6-(2-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid isopropylamide: To a 4 mL vial is placed6-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (25.0 mg, 0.07 mmol), resin-bound Hunigs base (81 mg,0.29 mmol, 3.54 mmol/g), resin bound DMAP (catalytic), and dry CH₂Cl₂and isopropyl isocyanate (16□L, 0.18 mmol). The vial is agitated bymeans of a lab quake shaker overnight. In the morning, PS-trisamine (120mg, 0.36 mmol, 3.0 mmol/g) is added and the reaction again allowed torotate for 4 hours to scavenge excess isocyanate., Filtration, washingwith CH₂Cl₂ and concentration afforded the desired urea. M+1 360.

[0175] In a similar manner Examples 179 is prepared:

EXAMPLE 179

[0176]6-(2-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid cyclohexylamide; M+1 400.

EXAMPLE 79

[0177][3-(2-Methanesulfonyl-1,2,3,4-tetrahydro-isoquinolin-6-yloxy)-propyl]-dimethyl-amine:To a 4 mL vial is placedDimethyl-[3-(1,2,3,4-tetrahydro-isoquinolin-6-yloxy)-propyl]-amine (24.0mg, 0.1 mmol), resin-bound DIEA (58 mg, 0.2 mmol, 3.54 mmol/g), MsCl (12□L, 0.15 mmol) and dry CH₂Cl₂ (2 mL). The vial is allowed to rotateovernight. In the morning, PS-trisamine (136 mg, 0.41 mmol, 3.0 mmol/g)is added and the reaction again allowed to rotate for 4 hours toscavenge excess MsCl. Filtration, washing with CH₂Cl₂ and concentrationaffords the desired urea LCMS>99% @ 230 nm and ELSD, M+1 360.

EXAMPLE 302

[0178]2-Benzenesulfonyl-6-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline:2-Benzenesulfonyl-6-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolineis prepared from6-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (330 mg, 0.95 mmol), NEt₃ (0.48 mL, 3.5 mmol), andbenzenesulfonyl chloride (0.15 mL, 1.17 mmol) via a proceduresubstantially analogous to Procedure F except that an additional SCXcolumn purification step is performed to give the product as a whitesolid (250 mg, 63% yld). MS(ES+) 415.3(M+H)⁺.

[0179] 5-Hydroxy-3,4-dihydro-1-H-isoquinoline-2-carboxylic acidtert-butyl ester is prepared by the procedures similar to thosedescribed in Durand S.; Lusinchi, X.; Moreau, R. C. Bull. Soc. Chim.France 1961, 207, 270; and Georgian, V.; Harrison, R. J.; Skaletzky, L.L.; J Org Chem 1962, 27, 4571.

EXAMPLE 290

[0180]5-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester is prepared from5-Hydroxy-3,4-dihydro-1-H-isoquinoline-2-carboxylic acid tert-butylester (5.69 g, 22.8 mmol) in a manner substantially analogous toProcedure A except DMF is used in place of dioxane. Following aqueousworkup, the crude material is purified by flash chromatography [Biotage65M SiO₂, elute 10% (25/5/1 CHCl₃/MeOH/NH₄OH)/90% (10% MeOH/CHCl₃)] togive the title compound (5.2 g, 61%). MS (ES+) 375.3

EXAMPLE 291

[0181] 5-(3-Piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride salt is prepared from5-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (4.0 g, 10.7 mmol) in a manner substantiallyanalogous to Procedure B to give the title compound as an off-whitesolid (3.47 g, 93%). MS (ES+) 275.2

EXAMPLE 309

[0182][5-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]-thiophen-2-yl-methanoneis prepared from5-(3-Piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride salt (0.256 g, 0.74 mmol) in a manner substantiallyanalogous to Procedure E to give the title compound as an off-whitesolid (0.109 g, 38%). MS (ES+) 415.2

EXAMPLE 294

[0183]2-Benzenesulfonyl-5-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolineis prepared from5-(3-Piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride salt (150 mg, 0.43 mmol) via a procedure substantiallyanalogous to Procedure F to provide the title compound as an off-whitesolid (54 mg, 30%). MS (ES+) 385.2

EXAMPLE 306

[0184]2-Ethyl-5-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline isprepared from5-(3-Piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride salt (375 mg, 1.1 mmol) in a manner substantiallyanalogous to Procedure C to give the title compound as a yellow oil (49mg, 15%). MS (ES+) 303.3

EXAMPLE 313

[0185]2-Cyclohexylmethyl-5-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolineis prepared from5-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolincdihydrochloride salt (350 mg, 1.0 mmol) in a manner substantiallyanalogous to Procedure C to give the title compound as a yellow oil(0.142 mg, 38%). MS (ES+) 371.4

[0186] 8-Methoxy-1,2,3,4-tetrahydro-isoquinoline is prepared accordingto Shanker, P. S.; Subba Rao, G. S. R. Indian J. of Chemistry section B1993, 32B, 1209-1213.

[0187] 8-Hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acidtert-butyl ester: To a mixture of8-methoxy-1,2,3,4-tetrahydro-isoquinoline (2.54 g, 15.6 mmol) in CH₂Cl₂(60 mL) at −78° C. is added a solution of boron tribromide in CH₂Cl₂ (1M, 52 mL, 52 mmol) dropwise over approximately 20 minutes. The coolingbath is removed, and the mixture is warmed to room temperature. After 4h, the reaction is carefully quenched with ice. EtOAc and water isadded, and the mixture is stirred overnight. The phases are separated,and 5 N NaOH solution is added to the aqueous phase until pH is basic.Dioxane (250 mL) and di-tert-butyl dicarbonate (6.78 g, 31 mmol) isadded, and reaction mixture is stirred at room temperature overnight.EtOAc is added, and the phases are separated. The aqueous phase isextracted with EtOAc (1×), and the combined organic phase is washed withbrine and dried (MgSO₄). After filtration, the solvent is removed invacuo to provide the title compound (4.84 g) that is used withoutpurification. MS (ES−) 248.2.

EXAMPLE 307

[0188]8-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester is prepared from8-hydroxy-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester(0.84 g, 3.4 mmol) in a manner substantially analogous to Procedure Aexcept DMF is used in place of dioxane. Following aqueous workup, thecrude material is purified by chromatography [SCX-MeOH wash, elute 2MNH₃/MeOH then Biotage 40s SiO₂, elute 10% (25/5/1 CHCl₃/MeOH/NH₄OH)/90%(10% MeOH/CHCl₃)] to give the title compound (0.61 g, 48%). MS (ES+)375.3.

EXAMPLE 308

[0189] 8-(3-Piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride salt is prepared from8-(3-piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (3.09 g, 8.25 mmol) in a manner substantiallyanalogous to Procedure B to give the title compound as an off-whitesolid (2.63 g, 85%). MS (ES+) 275.3

EXAMPLE 309

[0190]2-Cyclohexylmethyl-8-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolineis prepared from8-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride salt (0.375 g, 1.1 mmol) in a manner substantiallyanalogous to Procedure C to give the title compound as a yellow oil(0.195 g, 48%). MS (ES+) 371.4

EXAMPLE 310

[0191]2-Ethyl-8-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinoline isprepared from8-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride salt (0.375 g, 1.1 mmol) in a manner substantiallyanalogous to Procedure C to give the title compound as a yellow oil(0.124 g, 37%). MS (ES+) 303.3.

EXAMPLE 311

[0192]2-Benzenesulfonyl-8-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolineis prepared from8-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride salt (300 mg, 0.86 mmol) via a procedure substantiallyanalogous to Procedure F to provide the title compound as an off-whitesolid (0.22 g, 63%). MS (ES+) 415.3.

EXAMPLE 312

[0193][8-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-1H-isoquinolin-2-yl]-thiophen-2-yl-methanone:To a mixture of8-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride salt (300 mg, 0.86 mmol) and NEt₃ (0.36 mL, 2.6 mmol) inCH₂Cl₂ (10 mL) is added 2-thiophene carbonyl chloride (0.10 mL, 0.95mmol). After stirring at room temperature overnight, the mixture ispartitioned between EtOAc and water. The organic phase is washed withbrine, dried (MgSO₄), and concentrated. The residue is purified by flashchromatography [Biotage 40S SiO₂, elute 20% (90/10/1CH₂Cl₂/MeOH/NH₄OH)/80% CH₂Cl₂ to 100% (90/10/1 CH₂Cl₂/MeOH/NH₄OH)] toyield the title compound as a yellow oil (0.181 g, 55%). MS (ES+) 385.3.

EXAMPLE 206

[0194] 6-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-2H-isoquinolin-1-one isprepared from 6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (CAS RegistryNumber 22245-98-3) (0.5 g, 2.9 mmol) in a manner substantially analogousto Procedure A except DMF is used in place of dioxane. Following aqueousworkup, the crude material is purified by flash chromatography (Biotage40M SiO₂, elute 90/10/1 CH₂Cl₂/MeOH/NH₄OH) to give the title compound asa white solid (0.516 g, 61%). MS (ES+) 289.1

EXAMPLE 207

[0195] 7-(3-Piperidin-1-yl-propoxy)-3,4-dihydro-2H-isoquinolin-1-one isprepared from 7-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (CAS RegistryNumber 22246-05-5) (1.43 g, 8.76 mmol) in a manner substantiallyanalogous to Procedure A except DMF is used in place of dioxane.Following aqueous workup, the crude material is purified by flashchromatography (Biotage 40M SiO₂, elute 90/10/1 CH₂Cl₂/MeOH/NH₄OH) togive the title compound as a white solid (1.11 g, 44%). MS (ES+) 289.1

EXAMPLE 205

[0196] 7-(3-Pyrrolidin-1-yl-propoxy)-3,4-dihydro-2H-isoquinolin-1-one isprepared from 7-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (0.48 g, 2.94mmol) in a manner substantially analogous to Procedure A except DMF isused in place of dioxane and 1-(3-Chloro-propyl)-pyrrolidine is usedinstead of N-(3-chloropropyl)piperidine. Following aqueous workup, thecrude material is purified by flash chromatography (Biotage 40M SiO₂,elute 90/10/1 CH₂Cl₂/MeOH/NH₄OH) to give the title compound as anoff-white solid (0.17 g, 21%). MS (ES+) 275.1

[0197] 2-Ethyl-6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one:

[0198] To a mixture of 6-methoxy-3,4-dihydro-2H-isoquinolin-1-one (0.30g, 1.69 mmol) in THF (10 mL) is added sodium hydride (60% mineral oilsuspension, 100 mg). The suspension is heated at reflux for 1 h, andcooled to room temperature. Ethyl iodide (1.4 mL, 17 mmol) is added, andthe mixture is stirred at room temperature overnight. The mixture ispartitioned between EtOAc and water. After the aqueous phase isextracted with EtOAc (2×), the combined organic phase is washed withbrine and dried (MgSO₄). After removal of the solvent, the residue ispurified by flash chromatography (Biotage 40M SiO₂, elute 45%EtOAc:hexane−50% EtOAc:hexane, linear gradient) to yield2-ethyl-6-methoxy-3,4-dihydro-2H-isoquinolin-1-one as a colorless oil(0.275 g, 78%). The material is dissolved in CH₂Cl₂ (10 mL) and cooledto −78° C. To the cooled mixture is added a solution of boron tribromide(1 M, 4.7 mL, 4.7 mmol) in CH₂Cl₂. After 0.5 h, the temperature iswarmed to 0° C. and stirred for 3 h. After the reaction is carefullyquenched with ice, EtOAc and water is added, and the mixture isvigorously stirred overnight. The phases are separated, and the organicphase is extracted with EtOAc (2×). The combined organic phase is washedwith brine and dried (MgSO₄). The solvent is removed in vacuo, and theresidue is purified by chromatography (Varian 10 g SiO₂ cartridge, elute60% EtOAc:hexane) to provide2-ethyl-6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (0.209 g, 82%). MS(ES+) 192.0

EXAMPLE 265

[0199]2-Ethyl-6-(3-piperidin-1-yl-propoxy)-3,4-dihydro-2H-isoquinolin-1-one isprepared from 2-Ethyl-6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (0.192g, 1.0 mmol) in a manner substantially analogous to Procedure A exceptDMF is used in place of dioxane. Following aqueous workup, the crudematerial is purified by chromatography [Varian 10 g SiO₂ cartridge,elute 10% (25/5/1 CHCl₃/MeOH/NH₄OH)/90% (10% MeOH/CHCl₃)] to obtain thetitle compound as a waxy off-white solid (77 mg, 24%). MS (ES+) 317.1

EXAMPLE 303

[0200][3-Fluoro-4-(3-piperidin-1-yl-propoxy)-phenyl]-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone:

[0201] General Procedure G: A mixture of(3-Fluoro-4-hydroxy-phenyl)-(2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone(0.193 g, 0.66 Mmol), Cs₂CO₃ (0.43 g, 1.32 mmol), KI (55 mg, 0.33 mmol),and N-(3-chloropropyl)piperidine (3.9 g, 24 mmol) in DMF (5 mL) isheated at 90° C. overnight. The mixture is partitioned between EtOAc andwater. The phases are separated, and the aqueous phase is extracted withEtOAc (2×). The combined organic phase is washed with brine, dried(MgSO₄), and concentrated in vacuo. The residue is purified bychromatography [SCX-MeOH wash, elute 2M NH₃/MeOH; then Biotage 12M SiO₂,elute 10% (25/5/1 CHCl₃/MeOH/NH₄OH)/90% (10% MeOH/CHCl₃)] to give thetitle compound as a yellow oil (0.105 g, 38%). MS (ES+) 418.4

EXAMPLE 240

[0202] {1-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-cyclopropyl}-carbamicacid benzyl ester is prepared from[1-(4-Hydroxy-phenyl)-cyclopropyl]-carbamic acid benzyl ester (1.21 g,4.28 mmol), Cs₂CO₃ (2.78 g, 8.55 mmol), KI (71 mg, 0.43 mmol), andN-(3-chloropropyl)piperidine (0.86 g, 5.34 mmol) in dioxane (50 mL) in amanner substantially analogous to Procedure A to give the product((1.16g, 66%). MS (ES+) 409.3.

EXAMPLE 241

[0203] 1-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-cyclopropylamine:{1-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-cyclopropyl}-carbamic acidbenzyl ester (1.08 g, 2.65 mmol) is dissolved in ethanol (50 mL), and10% Pd/C is added (200 mg). The mixture was stirred under a balloon onhydrogen for 3 hours. The reaction mixture was stirred through a plug ofsilica gel to give the desired compound. HRMS 275.2123 (M+H)⁺.

EXAMPLE 247

[0204]2-Morpholin-4-yl-N-{1-[4-(3-piperidin-1-yl-propoxy)-phenyl]-cyclopropyl}-acetamide:1-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-cyclopropylamine (0.195 g, 0.72mmol) and morpholin-4-yl-acetic acid (0.125 g, 0.86 mmol) are dissolvedin DMF, and diisopropylethylamine added (0.15 mL), followed by EDC(0.165 g, 0.86 mmol) and HOBt (0.116 g, 0.86 mmol). The reaction mixturewas stirred overnight at room temperature. The residue is purified bychromatography [SCX-MeOH wash, elute 2M NH₃/MeOH; then Biotage 12M SiO₂,elute 10% (25/5/1 CHCl₃/MeOH/NH₄OH)/90% (10% MeOH/CHCl₃)] to give thetitle compound as a yellow oil. HRMS 402.2765 (M+H)⁺.

EXAMPLE 316

[0205]7-(4-Piperidin-1-yl-butoxy)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester: A 20 mL DMF mixture of7-(4-chloro-butoxy)-3,4-dihydro-1-H-isoquinoline-2-carboxylic acidtert-butyl ester (1.0 g, 3 mmol), piperidine (0.75 mL, 7.5 mmol), and KI(1.0 g, 6 mmol) is stirred at 50° C. under N₂ for four hours, then atroom temperature for 16 hours. The reaction mixture is directly purifiedby chromatography (SCX-MeOH wash, elute 2M NH3/MeOH; then SiO₂; 0-6%MeOHlCH₂Cl₂/1% NH₄OH gradient) to give the free base (700 mg, 60% yld).MS(ES+)389.3 (M+H)⁺ free base.

EXAMPLE 314

[0206] 7-(4-Piperidin-1-yl-butoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride:7-(4-Piperidin-1-yl-butoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride is prepared from7-(4-chloro-butoxy)-3,4-dihydro-1-H-isoquinoline-2-carboxylic acidtert-butyl ester (600 mg, 1.5 mmol) and 4N HCl/dioxane (2.5 mL, 10 mmol)base in a manner substantially analogous to Procedure B to give theproduct (490 mg, 90% yld). MS(ES+)389.3 (M+H)⁺ free

EXAMPLE 315

[0207]2-Ethyl-7-(4-piperidin-1-yl-butoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride:2-Ethyl-7-(4-piperidin-1-yl-butoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride is prepared from7-(4-piperidin-1-yl-butoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (252 mg, 0.7 mmol), and acetaldehyde (0.40 mL, 7 mmol)in a manner substantially analogous to Procedure C to give thedihydrochloride product as an off white solid (125 mg, 70% yld).MS(ES+)317.2(M+H)⁺ free base.

EXAMPLE 317

[0208]2-Cyclohexylmethyl-7-(4-piperidin-1-yl-butoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride:2-Cyclohexylmethyl-7-(4-piperidin-1-yl-butoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride is prepared from7-(4-piperidin-1-yl-butoxy)-1,2,3,4-tetrahydro-isoquinolinedihydrochloride (175 mg, 0.48 mmol), and cyclohexanecarboxaldehyde (0.35mL, 2.9 mmol) in a manner substantially analogous to Procedure C to givethe dihydrochloride product as an off white solid (105 mg, 62% yld).MS(ES+)385.3(M+H)⁺ free base.

EXAMPLE 208

[0209][3-(3-Piperidin-1-yl-propoxy)-benzyl]-(3-pyrrolidin-1-yl-propyl)-amine:The reductive amination is run with3-(3-piperidin-1-yl-propoxy)-benzaldehyde (1 g, 4 mmol) and),3-pyrrolridin-1-yl propylamine (1 mL, 8 mmol), and MP-CNBH₃ resin(4.5 g,10.4 mmol) via a procedure substantially analogous to[2-(3-piperidin-1-yl-propoxy)-benzyl]-(3-pyrrolidin-1-yl-propyl)-amineto give the product as a yellow oil (818 mg, 58% yld).MS(ES+)360.3(M+H)⁺ free base.

EXAMPLE 202

[0210][4-(4-Piperidin-1-yl-butoxy)-benzyl]-(2-pyrrolidin-1-yl-ethyl)-amine: An8 mL DMF solution of[4-(4-bromo-butoxy)-benzyl]-(2-pyrrolidin-1-yl-ethyl)-amine (307 mg,0.86 mmol) and piperidine (0.22 mL, 2.2 mmol) is stirred at 90° C. forsix hours under N₂. The reaction mixture is cooled, diluted with CH₂Cl₂,filtered, washed with brine, dried (Na₂SO₄), and concentrated. Theresidue is purified by chromatography (SiO₂; 0-6% MeOH/CH₂Cl₂/1% NH₄OHgradient) to give the product (40 mg, 12% yld). MS(ES+)360.4(M+H)⁺ freebase.

EXAMPLE 236

[0211] N-(2-Piperidin-1-yl-ethyl)-4-(3-piperidin-1-yl-propoxy)-benzamideis prepared according to general procedure A from4-Hydroxy-N-(2-piperidin-1-yl-ethyl)-benzamide (CAS Registry106018-38-6) (0.27 g, 1.1 mmol) to give the title compound as a whitesolid (77 mg, 19%). MS (ES+) 374.3

EXAMPLE 237

[0212]2-Fluoro-N-(2-piperidin-1-yl-ethyl)-4-(3-piperidin-1-yl-propoxy)-benzamide:To a mixture of 2-Fluoro-4-(3-piperidin-1-yl-propoxy)-benzoic acid (70mg, 0.25 mmol) and 1-(2-aminoethyl)piperidine (450 L, 0.3 mmol) in DMF(5 mL) was added EDC (58 mg, 0.3 mmol), HOBT (40 mg, 0.3 mmol), anddiisopropylethyl amine (52 □, 0.3 mmol). The mixture was stirred at roomtemperature overnight. The mixture was partitioned between EtOAc andwater. The organic phase was washed with brine, dried (MgSO₄), andconcentrated. The residue was purified by flash chromatography (Biotage12 M, elute 90/10/1 CH₂Cl₂/MeOH/NH₄OH) to yield the title compound. MS(ES+) 392.3

EXAMPLE 264

[0213]3-Fluoro-N-(2-piperidin-1-yl-ethyl)-4-(3-piperidin-1-yl-propoxy)-benzamideis prepared from 3-Fluoro-4-hydroxy-N-(2-piperidin-1-yl-ethyl)-benzamide(0.1 g, 0.38 mmol) by general procedure A to yield the title compound asan off-white solid (80 mg, 54%). MS (ES+) 392.2

EXAMPLE 256

[0214](2-Morpholin-4-yl-ethyl)-[4-(3-piperidin-1-yl-propoxy)-benzyl]-aminedihydrochloride: The dihydrochloride salt was prepared from(2-morpholin-4-yl-ethyl)-[4-(3-piperidin-1-yl-propoxy)-benzyl]-amine(0.307 g) by dissolving in THF (6 mL) and adding a solution of HCl inEt₂O (1 M, 0.85 mL). Additional Et₂O was added until the mixture wascloudy, and the mixture was allowed to stand at 0° C. overnight. Thewhite solid was collected by filtration to give the dihydrochloridesalt. Anal. Calculated for C₂₁H₃₅N₃O₂.2 HCl: C, 58.06; H, 8.58; N, 9.67;Cl, 16.32. Found: C, 58.0; H, 8.51; N, 9.57; Cl, 16.99.

Synthesis of (1)

[0215] 1.50 g of ® (+)-1-(4-methoxyphenyl) ethylamine (10.0 mmol), 2.06g of N,N-Dimethylglycine (20.0 mmol) and 2.58 g ofN,N-Di-isopropylethylamine (20.0 mmol) were dissolved in 50 ml of CH₂Cl₂and 6.78 g of PyBOP (13.0 mmol) was added to the mixture. The reactionmixture was stirred at room temperature for 4h. The reaction mixture wasdiluted with 20 ml of CH₂Cl₂ and washed with brine, 0.1N Hl, brinesatNaHCO3 and brine. The separated organic layer was dried over NaSO4and evaporated. The crude product was applied to short silica-gel columnchromatography (CH₂Cl₂→CH₂Cl₂: 2M NH3 in MeOH=20:1) and pure product wasrecrystalized from Et2O/CH₂Cl₂. White powder. 1.62 g (69%). C/MS:m/z237(M+1)

Synthesis of (2)

[0216] This compound was synthesized according to the method describedin the preparation of (1).

Synthesis of (3)

[0217] 500 mg of compound (1) (2.12 mmol) was dissolved in 5.0 ml ofCH₂Cl₂ and cooled to 0° C. 10.0 ml of BBr3 1.0M in CH₂Cl₂ (10 mmol) wasadded slowly and stirred at 0° C. for 1 h. MeOH was added to quench thereaction and 4.0 ml of 5NaOHaq. was added. The mixture was stirred at 0°C. for 10 min. CH₂Cl₂ layer was separated. The water layer was acidifiedslowly PH=14→2 and extracted with CH₂Cl₂ for each step. The water layerwas concentrated in vacuo, filtered off NaCl. The filtrate was made toPH=10 stepwise and extracted with CH₂Cl₂ each step. All of theseextractions were combined together, dried over NaSO4 and evaporated togive the product 301 mg (64%). LC/MS:m/z 223(M+1)

Synthesis of (4)

[0218] This compound was synthesized according to the method describedin the preparation of (3).

Synthesis of (5)

[0219] 52 mg of compound (3) (0.23 mmol), 57 mg of3-diethylaminopropanol (0.28 mmol) and 73 mg of Triphenylphosphine (0.28mmol) were dissolved in 2.0 ml of dry THF. The air was replaced to N₂gas. 37 mg of Diisopropyl-azodicarboxylate (0.28 mmol) in 0.5 ml of THFwas added to this reaction mixture and stirred at room temparature forovernight. The reaction mixture was concentrated and applied to SCXcolumn, washed by MeOH. The crude product was eluted with 2M NH3 inMeOH. This crude product was applied to silica-gel column chromatography(CH₂Cl₂: 2M NH3 in MeOH=20:1) to give the product. 48 mg (62%). LC/MS:m/z 336(M+1)

Synthesis of (6)

[0220] This compound was synthesized according to the method describedin the preparation of (5).

Synthesis of (7)

[0221] 3.0 ml of Litium aluminium hydride 1.0M in THF (3.0 mmol) wasplaced in flask and the air was replaced to N2gas. 43 mg of compound (5)(0.13 mmol) in 2.0 ml of THF was added slowly into the flask and stirredunder reflux for 2 h. The reaction mixture was allowed to cool to roomtemperature and water was added to quench the reaction. The organiclayer was decanted. The water layer was extracted with CH₂Cl₂ (3 times)and all organic layers were combined together. This solution was driedover NaSO4 and evaporated. The crude product was applied to silica-gelcolumn chromatography (CH₂Cl₂: 2M NH3 in MeOH=20:1) to give the product.19 mg (46%). LC/MS:m/z 322(M+1)

Synthesis of (8)

[0222] This compound was synthesized according to the method describedin the preparation of (7).

[0223] Synthesis of (10) 100 mg of compound (9) (0.50 mmol) and 116 mgof (R)(−)-1-(2-pyrrolidinylmethyl)pyrrolidine (0.75 mmol) were dissolvedin 5.0 ml of 5% AcOH in CH₂Cl₂ and 310 mg of MP-cyanoborohydride(mmo/g=2.42, 0.75 mmol) was added in the reaction vial. The vial wascapped by Teflon cap and shaken at 60° C. for overnight. The reactionmixture was filtered and the filtrate was concentrated under N2 gas. Thecrude product was applied to silica-gel column chromatography (CH₂Cl₂:2M NH3 in MeOH 20:1) to give the product. 143 mg (85%). LC/MS:m/z337(M+1)

Synthesis of Example 261

[0224] 65 mg of compound (10) (0.19 mmol) and 50 mg of piperidine (0.58mmol) were put into 4.0 ml vial and 2.0 ml of THF and 10 mg of NaI wereadded to the vial. The vial was capped by Teflon cap and heated at 100°C. for 3 days. The reaction mixture was concentrated under N2gas andapplied to silica-gel column chromatography (CH₂Cl₂: 2M NH3 inMeOH=20:1) to give the product. 38 mg (51%). LC/MS: m/z 386(M+1)

Synthesis of (15)

[0225] 813 mg of compound (14) (98536) (3.8 mmol) was dissolved in 5.0ml of thionyl chloride and stirred at 70° C. for 1 h under N2 gas. Theexcess acid chloride was removed in vacuo. The residue was dissolved in1.0 ml of CH₂Cl₂ to make acid chloride solution. 643 mg of(S)(+)-1(2-pyrrolidinylmethyl)pyrrolidine (4.17 mmol) and 421 mg oftriethylamine (4.17 mmol) were dissolved in 10 ml of CH₂Cl₂ and cooledto 0° C. Acid chloride solution was added to this mixture at 0° C. andstirred at room temperature for 2 h. The reaction mixture was dilutedwith CH₂Cl₂ and washed by brine. The crude product was applied tosilica-gel column chromatography (CH₂Cl₂: 2M NH3 in MeOH=10:1) to givethe product. 1.13 g (85%) LC/MS: m/z 351(M+1)

Synthesis of Example 209

[0226] This compound was synthesized according to the method describedin the preparation of Example 261.

Synthesis of (18)

[0227] 1.17 g of Na (51 mmol) was dissolved in 200 ml of MeOH and 6.48 gof methyl p-hydroxy benzoate (17) (42.5 mmol) was added followed by20.52 g of 1-bromo 4-chlorobutane (119.6 mmol). The reaction mixture wasstirred at room temperature for 2 h and stirred at 60° C. for 1 h.Almost of MeOH was removed in vacuo. The residue was dissolved in waterand acidified by cHCl to PH=1.0 and extracted with CH₂Cl₂. The separatedorganic layer was dried over NaSO4 and evaporated. The crude product wasapplied to silica-gel column chromatography (CH₂Cl₂: 2M NH3 inMeOH=20:1) to give the product. 1.64 g (17%). NMR (DMSO); 7.84(d, 2H,J=5.9 Hz), 6.91(d, 2H, J=5.9 Hz), 4.02(t, 2H, J=5.8 Hz), 3.69(t, 2H,J=6.4 Hz), 1.85(m, 4H)

Synthesis of (20)

[0228] 1.14 g of compound (19) (4.44 mmol) was dissolved in 15 ml ofMeOH and 10 ml of 5N NaOHaq. was added. The reaction mixture was stirredat room temperature for overnight. The reaction mixture was evaporated.The residue was dissolved in water and acidified by cHCl to PH=1.0. Thissolution was extracted with CH₂Cl₂, dried over NaSO4 and evaporated. Thepure product was recrystalized from Hexane/CH₂Cl₂. 829 mg (77%) NMR(DMSO); 8.05(d, 2H, J=8.9 Hz), 6.93(d, 2H, J=8.9 Hz), 4.05(t, 2H, J=6.3Hz), 3.57(t, 2H, J=6.8 Hz), 1.86(m, 4H), 1.65(m, 2H)

[0229] To a 4 mL vial was placed 101 (28,5 mg, 0.1 mmol), resin-boundDCC (170 mg, 0.1 mmol), resin-bound DCC (170 mg, 0.16 mmol, 0.94mmol/g), HOBt (16 mg, 0.12 mmol), amine (13 uL, 0.08 mmol) and a 5:1:1mixture of CHCl₃:CH₃CN:tBuOH. The vial was agitated by means of a labquake shaker overnight. In the morning, PS-trisamine (134 mg, 0.4 mmol,3.0 mmol/g) was added and the reaction again allowed to rotate overnightto scavenge excess carboxylic acid and HOBt. Filtration, washing withDCM/MeOH and concentration afforded a orange foam. Filtration through ashort pipet column provided 25 mg (83%) of an yellow solid, 629304. Massspec hit M+1, 386; LCMS>95% @230 nm and ELSD. A substantially analogousprocedure was employed for the array synthesis of Examples: Example #Observed Mass  41 361  42 361  44 389  43 401 130 386 131 386 132 401133 372 144 400 150 360 151 340 152 346 153 360 154 360 155 386 173 358

[0230]

[0231] 1-[4-(3-Piperidin-1-yl-propoxy)-phenyl]-butan-1-one

[0232] To a 20 mL vial was placed keto-phenol (500 mg, 3 mmol), CsCO₃(1.98 g, 6 mmol), KI (454 mg, 3 mmol) and chloropropylpiperdine (64 mg,3.3 mmol). Dioxane added and the reaction was heated to 90 degreesovernight on a J-KEM heater/shaker block. The reaction was then quenchedwith water, extracted into DCM and dried over Na2SO4. The material waspurified by Biotage utilizing 4:1 EtOAc:MeOH to afford (201) as a orangeoil (880 mg, 99%). Mass spec hit M+1, 290; LCMS>95% @230 nm and ELSD.

[0233] To a 20 mL vial was placed (102) (300 mg, 1 mmol), diamine (120mg, 1.14 mmol), MP-CNBH₃ (2.4 g, 6.22 mmol) and a 9:1 CHCl₃:HOAcsolution. The reaction was heated to 50 degrees overnight on a J-KEMheater/shaker block. The reaction was filtered, washed with DCM/MeOH.The material was then subjected to preparative HPLC purification toafford 29 mg (3%) of analytically pure example 94. as a white solid.Mass spec hit M+1, 362; LCMS>98% @230 nm and ELSD. Example 192 can bemade by a substantially analogous procedure, Observed mass 360. Thefollowing examples are made by a substantially analogous procedure:Phenyl Ketone Product Name Example (M + 1)

N-[6-(3-Dimethylamino-propoxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-N′,N′-dimethyl-ethane-1,2-diamine 84 320

N-[6-(3-Dimethylamino-2-methyl-propoxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]- N′,N′-dimethyl-ethane-1,2-diamine85 246 M − 87

N,N-Dimethyl-N′-[6-(1-methyl-piperidin-3-ylmethoxy)-1,2,3,4-tetrahydro-naphthalen- 1-yl]-ethane-1,2-diamine 86346

N-{1-[4-(3-Dimethylamino-2-methyl-propoxy)-phenyl]-propyl}-N′,N′-dimethyl- ethane-1,2-diamine 87 322

N-{1-[4-(3-Dimethylamino-2-methyl-propoxy)-phenyl]-butyl}-N′,N′-dimethyl- ethane-1,2-diamine 88 336

N,N-Dimethyl-N′-[6-(3-piperidin-1-yl-propoxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-ethane- 1,2-diamine 89 272 M − 87

N,N-Dimethyl-N′-[6-(2-piperidin-1-yl-ethoxy)-1,2,3,4-tetrahydro-naphthalen-1-yl]-ethane- 1,2-diamine 90 258 M − 87

N,N-Dimethyl-N′-{1-[4-(3-piperidin-1-yl-propoxy)-phenyl]-propyl}-ethane-1,2-diamine 91 348

N,N-Dimethyl-N′-{1-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-butyl}-ethane-1,2-diamine 92 334

N-{1-[4-(3-Dimethylamino-propoxy)-phenyl]-butyl}-N′,N′-dimethyl-ethane-1,2-diamine 93 322

N,N-Dimethyl-N′-{1-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-butyl}-ethane-1,2-diamine 95 348

[0234]

EXAMPLES 135, 14, 126 6

[0235] To a 10 mL round-bottom flask was added (102) (280 mg, 0.96 mmol)and dry MeOH (5 mL). Then, NaBH₄ (74 mg, 1.93 mmol) was added at roomtemperature. After 1 hour, the reaction was then quenched with water,extracted into DCM and dried over Na₂SO₄. The material was purified byBiotage utilizing 4:1 EtOAc:MeOH to provide 270 mg (98%) of a whitesolid. Mass spec hit M+1,292; LCMS>98% @230 nm and ELSD. Examples 14 and126 are made by a substantially analogous procedure. Observed mass:Example 14=321, Example 126 375.

EXAMPLE 142

[0236] To a round-bottom flask, equipped with stir bar and septum, wasplaced (103) (300 mg, 1.03 mmol), KI (230 mg, 1.54 mmol) and NaH (78 mg,95% dry, 3.09 μmmol). Then, dry DMF (20 mL, 0.5 M) was added via syringefollowed by chloroethylpiperidine (285 mg, 1.54 mmol). The reaction wasallowed to stir at 50 degrees overnight. In the morning, the reactionwas quenched with water, extracted into EtOAc (3×20 mL) and dried overbrine. Column chromatography in 9:1 DCM:MeOH afforded 631934 an yellowoil (300 mg, 79%). Mass sec hit M+1, 404; LCMS>95% @230 nm and ELSD.

EXAMPLE 246

[0237]

[0238] 3-Piperidinylpropanol (3.56 g, 25 mmoles) in 4 ml DMF was addedto a slurry of sodium hydride in 10 ml DMF at 0 C., and the reaction wasstirred at 0 C. for 0.5 hr. The 4-fluorobenzonitrile in 6 ml was addedat 0 C. The reaction was stirred at 0 C for 1 hr. and at RT overnight.Water and ether were carefully added. Separated the ether layer andextracted with water five times. The ether extract was dried over sodiumsulfate, filtered and evaporated to give 6.0 g (0.0246 mmoles, 98.4%yield). LCMS 1.61 min @254.0 nm 95.2%; @230.0 nm 89.5%; ELSD 1.71 min100%; MS 1.59 min M+1=245 good for product (104).

EXAMPLE 246

[0239] The nitrile (6.0 g, 0.0246 mmoles) in 250 ml 2B EtOH with 2.5 gRaNi was hydrogenated at 80 C. for 8 hrs. Filtration and evaporationyielded 5.4 g oil (88.4 yield).

EXAMPLE 217

[0240] The 1-hydroxybenzotriazole hydrate (13.5 mg, 0.1 mmole),1-piperidinepropionic acid (18.1 mg, 0.115 mmole), amine (248 mg, 0.1mmole), polystyrene-carbodiimide (125 mg, 0.15 mmoles) and 2.5 mlchloroform, acetonitrile, t-butanol (5:1:1) in a 4 ml vial were rotatedfor four days. Polysterene-trisamine (93.7 mg, 0.4 mmoles) was added andthe reaction was rotated overnight. Filtered reaction through filtercartridge and evaporated to give 37.5 mg, 0.0967 mmole, 96.7% yield.LCMS ELSD 1.42 min 100%, MS 1.21 min M+1=388 good for product. ExampleObserved Mass 116 348 117 376 118 350 119 384 120 391 121 322 122 398123 393 124 388 125 477

[0241]

EXAMPLE 15

[0242] The solution of diisopropylazodicarboxylate (3.93 ml, 20 mmoles)in 20 ml anhydrous THF was added dropwise with stirring to the coldsolution of 4-hydroxyacetophenone (2.18 g, 16 mmoles),3-diethylaminopropanol (2.23 ml, 15 mmoles) and triphenylphosphine (4.98g, 19 mmoles) in 50 ml anhydrous THF over 45 minutes. The reaction wasstirred in an ice bath for one hour and at room temperature for 18hours. The solvent was evaporated and ether was added. This solution wasextracted with dilute HCl (1.0 N) four times. These combined acidicextracts were extracted with ether, basified with a NaOH solution andextracted with ether three times. These combined ethereal extracts weredried over sodium sulfate, filtered and evaporated to give 3.41 g oil.LCMS 1.53 min @254.0 nm 97.4%; ELSD 1.59 min 91.1%; MS 1.58 min M+1=250good for product (105).

[0243] In a 7 ml vial with cap, 4-(3-diethylaminopropyloxy) acetophenone(0.47 g, 0.19 mmoles), N-(2-aminoethyl)morpholine (0.039 ml, 0.3 mmoles)and macroporus cyanoborohydride (169 mg, 0.4 mmoles) in 2 mldichloromethane with 0.2 ml glacial acetic were heated on shaker at 55°for 18 hours. Purified with a 3 ml extrelut cartridge hydrated with 3 mlwater. The reaction solution was added and the cartridge was rinsed withdichloromethane (5 ml). The product was eluted with 10%triethylamine/dichloromethane. LCMS 1.14 min @254.0 nm 95.6%; @230.0 nm95.3%; 1.20 min ELSD 95.3%; MS 1.14 min M+1=364 good for product.Example Observed Mass 15 364 16 348 17 308 18 362 19 336 20 377 21 391 1336 22 381 231 363 24 362 25 359 26 336 27 376

EXAMPLE 62

[0244]

[0245] The solution of diisopropylazodicarboxylate (3.93 ml, 20 mmoles)in 20 ml anhydrous THF was added dropwise with stirring to the coldsolution of 4-hydroxybenzaldehyde (1.95 g, 16 mmoles),3-diethylaminopropanol (2.23 ml, 15 mmoles) and triphenylphosphine (4.98g, 19 mmoles) in 50 ml anhydrous THF over 45 minutes. The reaction wasstirred in an ice bath for one hour and at room temperature for 18hours. The solvent was evaporated and ether was added. This solution wasextracted with dilute HCl (1.0 N) four times. These combined acidicextracts were extracted with ether, basified with a NaOH solution andextracted with ether three times. These combined ethereal extracts weredried over sodium sulfate, filtered and evaporated to give 3.71 g oil.LCMS 1.47 min @254.0 nm 97.0%; ELSD 1.53 min 95.4%; MS 1.48 min M+1=236good for product.

[0246] In a 7 ml vial with cap, 4-(3-diethylaminopropyloxy)benzaldehyde(0.59 g, 0.25 mmoles), N-(2-aminoethyl)morpholine (0.049 ml, 0.375mmoles) and macroporus cyanoborohydride (210 mg, 0.5 mmoles) in 3 mldichloromethane with 0.3 ml glacial acetic were heated on shaker at 40°briefly. Purified with 3 ml extrelut cartridge hydrated with 3 ml water.The reaction was added and the cartridge was rinsed with dicloromethane(5 ml). The product was eluted with 10% triethylamine/dichloromethane.LCMS 1.14 min ELSD 95.3%; MS 1.09 min M+1=350 good for product Example62. Example Observed Mass 629 350 63 334 47 294 48 348 49 348 50 322 51363 52 377 61 322 53 349 54 348 70 345 71 322 72 362 73 364 59 376 74348 104 320 113 420 114 410 107 334 103 334

EXAMPLE 45

[0247]

[0248] 4-Hydroxybenzaldehyde (2.44 g, 20 mmoles),N-(3-Chloropropyl)piperidine hydrochloride, cesium carbonate (19.7 g, 60mmoles) and potassium iodide in 14 ml dioxane with 0.7 ml water werestirred at 850 for 8 hours and at room temperature for 16 hours.Evaporated the decanted supernatant, added water to both (evaporatedsupernatant and solid) and extracted three times with ether. Thesecombined ethereal extracts were washed three times with water, driedover sodium sulfate, filtered and evaporated to give 7.8 g oil. LCMS1.48 min @254.0 nm 99.4%; @230.0 nm 89.6%; 1.51 min ELSD 99.4%; MS 1.49min M+1=248 good for product. 300 mHz NMR(CDCl₃) good for structure(107).

[0249] In a 7 ml vial with cap,4-[(3-N-piperidinyl)propyloxy]benzaldehyde (0.062 g, 0.25 mmoles),N-(2-aminoethyl)morpholine (0.049 ml, 0.375 mmoles) and macroporuscyanoborohydride (210 mg, 0.5 mmoles) in 3 ml dichloromethane with 0.3ml glacial acetic were heated on shaker at 400. The reaction was shakenat room temperature for 16 hours and at 400 for one hour. Purified with3 ml extrelut cartridge hydrated with 3 ml water. The reaction solutionwas added and the cartridge was rinsed with dicloromethane (5 ml). Theproduct was eluted with 10% triethylamine/dichloromethane. LCMS 1.13 min@230.0 nm 97.3%; 1.19 min ELSD 98.5%; MS 1.13 min M+1=362 good forproduct Example 45. Example Observed Mass 45 362 46 346 64 306 65 360 66360 67 334 68 361 69 360 55 357 56 334 57 374 58 376 75 388 60 360 102346 105 332 112 432 115 410 106 346 108 375 109 389 110 334

EXAMPLE 100

[0250]

[0251]Dimethyl-(2-{4-[1-(2-piperidin-1-yl-ethylamino)-ethyl]-phenoxy}-propyl)-amineTo a 20 mL vial was placed (108)(42 mg, 0.19 mmol), amine (37 mg, 0.29mmol), MP-CNBH₃ (190 mg, 0.45 mmol, 2.37 mmol/g) and a 9:1 CHCl₃:HOAcsolution. The reaction was heated to 50 degrees overnight on a J-KEMheater/shaker block. The reaction was filtered, washed with DCM/MeOH.The material was then subjected to preparative HPLC purification toafford 5.8 mg (9%) example 100. As a clear oil. Mass spec hit M+1, 334;LCMS>89% @214 nm.

[0252] In a procedure substantially similar to that for synthesis ifExample 100, the following examples are made: Amino Ketone Amine ProductName Example MS

Dimethyl-[3-(4-{1-[3-(2-methyl- piperidin-1-yl)-propylamino]-ethyl}-phenoxy)-propyl]-amine   13 613123 362

N-{1-[4-(3-Dimethylamino-propoxy)- phenyl]-ethyl}-N′-ethyl-N′-m-tolyl-ethane-1,2-diamine   12 613021 384

(1-{1-[4-(3-Dimethylamino-propoxy)- phenyl]-ethyl}-pyrrolidin-3-yl)-dimethyl-amine   11 613011 320

Dimethyl-(3-{4-[1-(1-phenyl-ethyl amino)-ethyl]-phenoxy}- propyl)-amine  10 327

Dimethyl-(3-{4-[1-(2-morpholin-4-yl- ethylamino)-ethyl]-phenoxy}-propyl)-amine   96 623901 335

N⁴-{1-[4-(3-Dimethylamino-propoxy) phenyl]-ethyl}-N¹,N¹-diethyl-pentane-1,4-diamine   97 363

[3-(4-{1-[(1-Ethyl-pyrrolidin-2-yl methyl)-amino]-ethyl}-phenoxy)-propyl]-dimethyl-amine   98 623903 333

(1-Benzyl-piperidin-4-yl)-{1-[4-(3- dimethylamino-propoxy)-phenyl]-ethyl}-amine   99 395

Dimethyl-(3-{4-[1-(2-piperidin-1-yl- ethylamino)-ethyl]-phenoxy}-propyl)-amine   100 333

(3-{4-[1-(3-Azepan-1-yl-propyl amino)-ethyl]-phenoxy}-propyl)-dimethyl-amine   101 361

{1-[4-(3-Piperidin-1-yl-propoxy)- phenyl]-ethyl}-pyridin-2-ylmethyl-amine   36 354

{1-[4-(3-Piperidin-1-yl-propoxy)- phenyl]- thyl}-pyridin-4-ylmethyl-amine   37 354

{1-[4-(3-Piperidin-1-yl-propoxy)- phenyl]-ethyl}-(tetrahydro-furan-2-ylmethyl)-amine   40 347

[0253]

EXAMPLE 29

[0254]N-{1-[4-(3-Diethylamino-propoxy)-phenyl]-ethyl}-N-(2-dimethylamino-ethyl)-C-phenyl-methanesulfonamide.To a 4 ml vial was placedN-{1-[4-(3-Diethylamino-propoxy)-phenyl]-ethyl}-N′,N′-dimethyl-ethane-1,2-diamine(22 mg, 0.07 mmol), phenyl-methanesulfonyl chloride (27 mg, 0.14 mmol),PS-DMAP (93 mg, 1.48 mmol/g), and CH₂Cl₂ (1.5 ml). The vial was agitatedby means of a lab quake shaker for 4 h. To the solution was addedPS-Trisamine (100 mg, 3.3 mmol, 3.0 mmol/g) and the reaction was allowedto agitate overnight to scavenge excess methansulfonyl chloride.Filtration, washing with CH₂Cl₂ and concentrating affordedN-{1-[4-(3-Diethylamino-propoxy)-phenyl]-ethyl}-N-(2-dimethylamino-ethyl)-C-phenyl-methanesulfonamide.Mass spec hit M+1, 476: LCMS>93% @ 230 nm and ELSD. Sulfonyl ChlorideProduct Name Example MS (M + 1)

N-{1-[4-(3-Diethylamino-propoxy)-phenyl]-ethyl}-N-(2-dimethylamino-ethyl)-benzenesulfonamide 30 462

Thiophene-2-sulfonic acid {1-[4-(3- diethylamino-propoxy)-phenyl]-ethyl}-(2-dimethylamino-ethyl)-amide 33 468

2,2,2-Trifluoro-ethanesulfonic acid {1-[4-(3-diethylamino-propoxy)-phenyl]-ethyl}- (2-dimethylamino-ethyl)-amide 31468

[0255] Utilizing the procedures provided herein, in addition to methodsknown in the art, compounds of Formula I and Formula II were prepared.Structural figures for representative examples of Formula I and FormulaII are shown the following pages. Example Observed Number Structure Mass1

336 2

321.2 3

4

5

321.2 6

400.2 7

210.3 8

9

308 10

327 11

320 12

384 13

362 14

321 15

363 16

348 17

308 18

362 19

336 20

377 21

391 22

381 23

376 24

362 25

359 26

336 27

376 28

362 29

476 30

462 31

468 32

33

468 34

35

335 36

354 37

354 38

39

40

235 41

361 42

361 43

401 44

389 45

362 46

346 47

294 48

348 49

348 50

322 51

363 52

377 53

349 54

348 55

357 56

334 57

374 58

376 59

376 60

360 61

322 62

350 63

334 64

306 65

360 66

360 67

334 68

361 69

360 70

345 71

322 72

362 73

364 74

348 75

388 76

263 77

320 78

474 79

360 80

292 81

346 82

326 83

326 84

85

246 86

346 87

322 88

336 89

272 90

258 91

348 92

334 93

322 94

362 95

348 96

335 97

363 98

333 99

393 100

334 101

361 102

346 103

334 104

320 105

332 106

346 107

334 108

375 109

389 110

334 111

364.1 112

432 113

420 114

410 115

410 116

348 117

376 118

350 119

384 120

391 121

322 122

398 123

393 124

388 125

477 126

375 127

375 128

275 129

303 130

386 131

386 132

401 133

372 134

315 135

292 136

386 137

250 138

317 139

389 140

289 141

317 142

404 143

331 144

400 145

329 146

357 147

371 148

359 149

317 150

360 151

340 152

346 153

360 154

360 155

386 156

386 157

383 158

368 159

363 160

385 161

402 162

386 163

386 164

361 165

261 166

289 167

322 168

303 169

315 170

343 171

357 172

345 173

358 174

306 175

360 176

386 177

346 178

360 179

400 180

292 181

377 182

332 183

344 184

358 185

372 186

346 187

385 188

373 189

320 190

306 191

320 192

360 193

381 194

381 195

381 196

371 197

420 198

336 199

320 200

334 201

322 202

360.4 203

360.2 204

360.4 205

275.1 206

289.1 207

289.1 208

360.3 209

400 210

386 211

388 212

415 213

422 214

400 215

360 216

418 217

303.3 218

404 219

395 220

334 221

362 222

359 223

410 224

405 225

489 226

413 227

414 228

375.3 229

429 230

414 231

402 232

400 233

414 234

374 235

372 236

374.3 237

329.2 238

275.3 239

400 240

409.3 241

275.2 242

401 243

418 244

317.2 245

289.1 246

247

402.3 248

249

415.1 250

303.3 251

400 252

415 253

386 254

422 255

388 256

362.2 257

385.1 258

259

400 260

415 261

386 262

401 263

386 264

392.2 265

317.1 266

360.2 267

381.1 268

421.1 269

400 270

415 271

303.3 272

273

371.4 274

360.5 275

317.1 276

471.1 277

457.1 278

440.1 279

280

281

318 282

400 283

372 284

353.2 285

433.2 286

445.2 287

458.2 288

386 289

386 290

375.3 291

275.2 292

371.4 293

415.2 294

385.2 295

400 296

402 297

414 298

416 299

334 300

348 301

374 302

415.3 303

418.4 304

433.2 305

433.2 306

303.3 307

375.3 308

275.3 309

371.4 310

303.3 311

415.3 312

385.3 313

371.4 314

389.3 315

317.2 316

389.3 317

385.3 318

428 319

443 320

414 321

416 322

428 323

450 324

388

[0256] The compound of Formula I is preferably formulated in a unitdosage form prior to administration. Therefore, yet another embodimentof the present invention is a pharmaceutical composition comprising acompound of Formula I and one or more pharmaceutically acceptablecarriers, diluents or excipients.

[0257] The present pharmaceutical compositions are prepared by knownprocedures using well-known and readily available ingredients. In makingthe formulations of the present invention, the active ingredient(Formula I compound) will usually be mixed with a carrier, or diluted bya carrier, or enclosed within a carrier which may be in the form of acapsule, sachet, paper or other container. When the carrier serves as adiluent, it may be a solid, semisolid or liquid material that acts as avehicle, excipient, or medium for the active ingredient. Thus, thecompositions can be in the form of tablets, pills, powders, lozenges,sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups,aerosol (as a solid or in a liquid medium), soft and hard gelatincapsules, suppositories, sterile injectable solutions and sterilepackaged powders.

[0258] Some examples of suitable carriers, excipients, and diluentsinclude lactose, dextrose, sucrose, sorbitol, mannitol, starches, gumacacia, calcium phosphate, alginates, tragacanth, gelatin, calciumsilicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose,water syrup, methyl cellulose, methyl and propylhydroxybenzoates, talc,magnesium stearate and mineral oil. The formulations can additionallyinclude lubricating agents, wetting agents, emulsifying and suspendingagents, preserving agents, sweetening agents or flavoring agents. Thecompositions of the invention may be formulated so as to provide quick,sustained or delayed release of the active ingredient afteradministration to the patient.

[0259] The compositions of the present invention may be formulated insustained release form to provide the rate controlled release of any oneor more of the components or active ingredients to optimize thetherapeutic effects, i.e., antihistaminic activity and the like.Suitable dosage forms for sustained release include layered tabletscontaining layers of varying disintegration rates or controlled releasepolymeric matrices impregnated with the active components and shaped intablet form or capsules containing such impregnated or encapsulatedporous polymeric matrices.

[0260] Liquid form preparations include solutions, suspensions andemulsions. As an example may be mentioned water or water-propyleneglycol solutions for parenteral injections or addition of sweeteners andopacifiers for oral solutions, suspensions and emulsions. Liquid formpreparations may also include solutions for intranasal administration.

[0261] Aerosol preparations suitable for inhalation may includesolutions and solids in powder form, which may be in combination with apharmaceutically acceptable carrier such as inert compressed gas, e.g.nitrogen.

[0262] For preparing suppositories, a low melting wax such as a mixtureof fatty acid glycerides such as cocoa butter is first melted, and theactive ingredient is dispersed homogeneously therein by stirring orsimilar mixing. The molten homogeneous mixture is then poured intoconvenient sized molds, allowed to cool and thereby solidify.

[0263] Also included are solid form preparations which are intended tobe converted, shortly before use, to liquid form preparations for eitheroral or parenteral administration, Such liquid forms include solutions,suspensions and emulsions.

[0264] The compounds of the invention may also be deliverabletransdermally. The transdermal compositions may take the form of creams,lotions, aerosols and/or emulsions and can be included in a transdermalpatch of the matrix or reservoir type as a re conventional in the artfor this purpose.

[0265] Preferably the compound is administered orally.

[0266] Preferably, the pharmaceutical preparation is in a unit dosageform. In such form, the preparation is subdivided into suitably sizedunit doses containing appropriate quantities of the active components,e.g., an effective amount to achieve the desired purpose.

[0267] The quantity of the inventive active composition in a unit doseof preparation may be generally varied or adjusted from about 0.01milligrams to about 1,000 milligrams, preferably from about 0.01 toabout 950 milligrams, more preferably from about 0.01 to about 500milligrams, and typically from about 1 to about 250 milligrams,according to the particular application. The actual dosage employed maybe varied depending upon the patient's age, sex, weight and severity ofthe condition being treated. Such techniques are well known to thoseskilled in the art. Generally, the human oral dosage form containing theactive ingredients can be administered 1 or 2 times per day.

[0268] Utility

[0269] Compounds of Formula I are effective as histamine H3 receptorantagonists. More particularly, these compounds are selective histamineH3 receptor antagonists that have little or no affinity for histaminereceptor GPRv53(H4R). As selective antagonists, the compounds of FormulaI are useful in the treatment of diseases, disorders, or conditionsresponsive to the inactivation of the histamine H3 receptor, includingbut not limited to obesity and other eating-related disorders. It ispostulated that selective antagonists of H3R will raise brain histaminelevels and possibly that of other monoamines resulting in inhibition offood consumption while minimizing peripheral consequences. Although anumber of H3R antagonists are known in the art, none have proven to besatisfactory obesity drugs. There is increasing evidence that histamineplays an important role in energy homeostasis. Histamine, acting as aneurotransmitter in the hypothalamus, suppressed appetite. Histamine isan almost ubiquitous amine found in many cell types and it binds to afamily of G protein-coupled receptors (GPCRs). This family provides amechanism by which histamine can elicit distinct cellular responsesbased on receptor distribution. Both the H1R and H2R are widelydistributed. H3R is primarily expressed in the brain, notably in thethalamus and caudate nucleus. High density of expression of H3R wasfound in feeding center of the brain. A novel histamine receptor GPRv53has been recently identified. GPRv53 is found in high levels inperipheral white blood cells; only low levels have been identified inthe brain by some investigators while others cannot detect it in thebrain. However, any drug discovery effort initiated around H3R mustconsider GPRv53 as well as the other subtypes.

[0270] The inventive compounds can readily be evaluated by using acompetitive inhibition Scintillation Proximity Assay (SPA) based on aH3R binding assay using [3H] a methylhistamine as ligand. Stable celllines, including but not limited to HEK can be transfected with cDNAcoding for H3R to prepare membranes used for the binding assay. Thetechnique is illustrated below (Example 3) for the histamine receptorsubtypes.

[0271] Membranes isolated as described in Example 3 were used in a[³⁵S]GTPχS functional assay. Binding of [³⁵S]GTPχS to membranesindicates agonist activity. Compounds of the invention of Formula I weretested for their ability to inhibit binding in the presence of agonists.Alternately, the same transfected cell lines were used for a cAMP assaywherein H3R agonists inhibited forskolin-activated synthesis of cAMP.Compounds of Formula I were tested for their ability to permitforskolin-stimulated cAMP synthesis in the presence of agonist.

[0272] Preparation of Histamine Receptor Subtype Membranes

[0273] A. Preparation H1R Membranes

[0274] cDNA for the human histamine 1 receptor (H1R) was cloned into amammalian expression vector containing the CMV promoter (pcDNA3.1 (+),Invitogen) and transfected into HEK293 cells using the FuGENETranfection Reagent (Roche Diagnostics Corporation). Transfected cellswere selected using G418 (500 μ/ml). Colonies that survived selectionwere grown and tested for histamine binding to cells grown in 96-welldishes using a scintillation proximity assay (SPA) based radioligandbinding assay. Briefly, cells, representing individual selected clones,were grown as confluent monolayers in 96-well dishes (Costar ClearBottom Plates, #3632) by seeding wells with 25,000 cells and growing for48 hours (37° C., 5% CO₂). Growth media was removed and wells wererinsed two times with PBS (minus Ca²⁺ or Mg²⁺). For total binding, cellswere assayed in a SPA reaction containing 50 mM Tris-HCL (assay buffer),pH 7.6, 1 mg wheat germ agglutinin SPA beads (Amersham PharmaciaBiotech, #RPNQ0001), and 0.8 nM ³H-pyrilamine (Net-594, NEN) (totalvolume per well=200 μl). Astemizole (10 μM, Sigma #A6424) was added toappropriate wells to determine non-specific binding. Plates were coveredwith FasCal and incubated at room temperature for 120 minutes. Followingincubation, plates were centrifuged at 1,000 rpm (˜800g) for 10 minutesat room temperature. Plates were counted in a Wallac Trilux 1450Microbeta scintillation counter. Several clones were selected aspositive for binding, and a single clone (H1R40) was used to preparemembranes for binding studies. Cell pellets, representing ˜10 grams,were resuspended in 30 ml assay buffer, mixed by vortexing, andcentrifuged (40,000 g at 4° C.) for 10 minutes. The pellet resuspension,vortexing, and centrifugation was repeated 2 more times. The final cellpellet was reusupened in 30 ml and homogenized with a Polytron TissueHomogenizer. Protein determinations were done using the Coomassie PlusProtein Assay Reagent (Pierce). Five micrograms of protein was used perwell in the SPA receptor-binding assay.

[0275] B. Preparation H2R Membranes

[0276] cDNA for the human histamine 2 receptor was cloned, expressed andtransfected into HEK 293 cells as described above. Histamine binding tocells was assayed by SPA described above. For total binding, cells wereassayed in a SPA reaction containing 50 mM Tris-HCl (assay buffer), pH7.6, 1 mg wheat germ agglutinin SPA beads (Amersham Pharmacia Biotech,#RPNQ0001), and 6.2 nM ³H-tiotidine (Net-688, NEN) (total volume perwell=200 μl). Cimetidine (10 μM, Sigma #C4522) was added to appropriatewells to determine non-specific binding.

[0277] Several clones were selected as positive for binding, and asingle clone (H2R10) was used to prepare membranes for binding studies.Five micrograms of protein was used per well in the SPA receptor-bindingassay.

[0278] C. Preparation of H3R Membranes

[0279] cDNA for the human histamine 3 receptor was cloned and expressedas described in Example 1, above. Transfected cells were selected usingG418 (500 μ/ml), grown, and tested for histamine binding by the SPAdescribed above. For total binding, cells were assayed in a SPA reactiondescribed above containing 50 mM Tris-HCL (assay buffer), pH 7.6, 1 mgwheat germ agglutinin SPA beads (Amersham Pharmacia Biotech, #RPNQ0001),and 1 nM (3H)-n-alpha-methylhistamine (NEN, NET1027) (total volume perwell=200 μl). Thioperimide was added to determine non-specific binding.Several clones were selected as positive for binding, and a single clone(H3R8) was used to prepare membranes for binding studies describedabove. Five micrograms of protein was used per well in the SPAreceptor-binding assay.

[0280] All compounds set forth in examples 1 to 322 exhibited affinityfor the H3 receptor greater than 1 uM. Preferred compounds of theinvention exhibited affinity for the H3 receptor greater than 200 nM.Most preferred compounds of the invention exhibit affinity for the H3receptor greater than 20 nM.

[0281] D. Preparation of GPRv53 Membranes

[0282] cDNA for the human GPRv53 receptor was cloned and expressed asdescribed in Example 1, above. Transfected cells were selected, testedfor histamine binding, and selected. HEK293 GPRv53 50 cells were grownto confluency in DMEM/F12 (Gibco) supplemented with 5% FBS and 500 ug/mlG418 and washed with Delbecco's PBS (Gibco) and harvested by scraping.Whole cells were homogenized with a Polytron tissuemizer in bindingbuffer, 50 mM Tris pH 7.5. Cell lysates, 50 ug, were incubated in 96well dishes with 3 nM (3H) Histamine and compounds in binding buffer for2 hours at room temperature. Lysates were filtered through glass fiberfilters (Perkin Elmer) with a Tomtec cell harverster. Filters werecounted with melt-on scintillator sheets (Perkin Elmer) in a WallacTrilux 1450 Microbeta Scintillation counter for 5 minutes.

[0283] Pharmacological Results

[0284] cAMP ELISA

[0285] HEK293H3R8 cells prepared as described above were seeded at adensity of 50,000 cells/well and grown overnight in DMEMIF12 (Gibco)supplemented with 5% FBS and 500 ug/ml G418. The next day tissue culturemedium was removed and replaced with 50 μl cell culture mediumcontaining 4 mM 3-isobutyl-1-methylxanthine (Sigma) and incubated for 20minutes at room temperature. Antagonist were added in 50 μl cell culturemedium and incubated for 20 minutes at room temperature. Agonist R(−)αmethylhistamine (RBI) at a dose response from 1×10⁻¹⁰ to 1×10⁻⁵ M wasthen added to the wells in 50 μl cell culture medium and incubated for 5minutes at room temperature. Then 50 μl of cell culture mediumcontaining 20 μM Forskolin (Sigma) was added to each well and incubatedfor 20 minutes at room temperature. Tissue culture medium was removedand cells were lysed in 0.1M HCl and cAMP was measured by ELISA (AssayDesigns, Inc.).

[0286] [³⁵S] GTPγ [S] Binding Assay

[0287] Antagonist activity of selected compounds was tested forinhibition of [³⁵S] GTP γ [S] binding to H3R membranes in the presenceof agonists. Assays were run at room temperature in 20 mM HEPES, 100 mMNaCl,5 mM MgCl₂ and 10 uM GDP at pH 7.4 in a final volume of 200 ul in96-well Costar plates. Membranes isolated from H3R8-expressing HEK293cell line (20 ug/well) and GDP were added to each well in a volume of 50μl assay buffer. Antagonist was then added to the wells in a volume of50 μl assay buffer and incubated for 15 minutes at room temperature.Agonist R(−) alpha methylhistamine (RBI) at either a dose response from1×10⁻¹⁰ to 1×10⁻⁵ M or fixed concentration of 100 nM were then added tothe wells in a volume of 50 μl assay buffer and incubated for 5 minutesat room temperature. GTP γ [³⁵S] was added to each well in a volume of50 μl assay buffer at a final concentration of 200 pM, followed by theaddition of 50 μl of 20 mg/ml WGA coated SPA beads (Amersham). Plateswere counted in Wallac Trilux 1450 Microbeta scintillation counter for 1minute. Compounds that inhibited more than 50% of the specific bindingof radioactive ligand to the receptor were serially diluted to determinea K[i](nM). The results are given below the indicated compound. TABLE 1Compound Ki (nM) Structure Example 2 1.48, 0.95

Example 1 1.4

[0288] To investigate the selectivity of the antagonists for thehistamine receptors, a competitive binding assay described above wasperformed. The ability of example 131 and 250 (structures given above)to selectively inhibit binding to H3R, HIR, H2 and H4R was determined.Importantly, the identification of H3R-specific antagonists that do bindthe newly identified H4R was demonstrated. Until the present invention,most known H3R antagonists also bound H4R. As demonstrated in Table 2,example 131 and example 250 did not inhibit binding H4R compare to H3R.To our knowledge, the study in Table 2 is the first demonstration of aH3R specific antagonist. TABLE 2 Ki (nM) Compound H3R H4R H1R H2 Example131 1.05 ≧20,000 ≧20,000 ≧20,000 Example 250 0.37 ≧20,000 1022 1109

[0289] Non-imidazole containing histamine H3 receptor antagonistsdisclosed in the literature generally have very poor pharmacokineticproperties (see J. Apelt, et al, J. Med. Chem. 2002,45,1128-1141).Compounds of this invention have markedly and unexpectedly improvedpharmacokinetic properties. Male Sprague Dawley Rats (n=3 per dose arm)were separately dosed with 3 mg/kg iv or 10 mg/kg po of compoundexamples 131 and 271 (vehicle: 5% ethanol/water or water respectively;dose volume: 1 mL/kg iv, 10 mL/kg po). Approximately 0.5 mL of blood wascollected in heparin collection tubes at multiple time points over an 8or 24-hour period for examples 131 and 271 respectively, and the sampleswere analyzed using LC/MS/MS. In this manner compound example 131 wasfound to have an oral bioavailability of 58% (AUC 0-24 hr; po/iv ratio)and an oral half-life of 10.4±4.2 hours (±SEM). Compound example 271 wasfound to have an oral bioavailability of 69% (AUC0-24 hr; po/iv ratio)and an oral half-life of 71.9±3.3 hours (±SEM).

[0290] From the above description, one skilled in the art can ascertainthe essential characteristics of the present invention, and withoutdeparting from the spirit and scope thereof, can make various changesand modifications of the invention to adapt it to various usages andconditions. Thus, other embodiments are also within the claims.

What is claimed is:
 1. A compound structurally represented by Formula I

or pharmaceutically acceptable salts thereof wherein: X is O, NR⁷ or S;R¹ is hydrogen, C₁-C₈ alkyl optionally substituted with 1 to 4 halogens,(CHR⁵)_(n)—C₃-C₇ cycloalkyl, (CHR⁵)_(n) aryl, (CHR⁵)_(n) heteroaryl, or(CHR⁵)_(n)—O(CHR⁵)_(n)-aryl; R² is independently R¹, or COR¹, orcyclized with the attached nitrogen atom at the R¹ position to form a 4,5, or 6 member carbon ring, wherein one of said carbons is optionallyreplaced by one of O, S, NR¹ or CO, or wherein the ring formed by R¹ andR² is optionally substituted one to two times with C₁-C₄ alkyl; R³ isindependently C₃-C₇ cycloalkylene, or C₁-C₄ alkylene optionallysubstituted; R⁴ is hydrogen, halogen, C₁-C₄ alkyl, (CHR⁵)_(n)—C₃-C₇cycloalkyl, (CHR⁵)_(n) aryl, (CHR⁵)_(n) heteroaryl,(CHR⁵)_(n)—O(CHR⁵)_(r)-aryl or CO or cyclized with R⁵ to from acyclopropyl ring; R⁵ is hydrogen, or C₁-C₄ alkyl; R⁶ is hydrogen, haloor cyclized with the attached carbon atom at the R⁵ position to form a 5to 6 member carbon ring, cyclized with the attached carbon atom at theR⁷ position to form a 5 to 6 member heterocyclic ring or R⁷ is hydrogen,C₁-C₈ alkyl optionally substituted with 1 to 4 halogens,(CHR⁵)_(n)—C₃-C₇ cycloalkyl, (CHR⁵)_(n) aryl, (CHR⁵)_(n) heteroaryl,(CHR⁵)—O(CHR⁵)_(n)-aryl, SO₂R¹ or Cyclized with attached carbon on R⁸ tofrom a 5, 6, or 7 membered carbon ring optionally substituted with R⁹,CF₃, or CN, optionally one of the said carbons is replaced by N, NR¹,CO; R⁸ is hydrogen, a bond, C₁-C₈ alkyl —SO₂ R⁹, —CO₂ R¹⁰, —CO R⁹, —CONHR¹⁰; R⁹ is hydrogen, halogen, C₁-C₈ alkyl optionally substituted with 1to 4 halogens, C₃-C₇ cycloalkyl, aryl, CH₂ aryl, heteroaryl,heterocycle, —O(CHR⁵)_(n)-aryl, —COR¹, —CONR¹ R², —SO₂R¹, —OR¹, —N(R¹)₂,NR¹R², —CH₂NR¹, R², —CONR¹R² —NHSO₂R¹, —NO₂, —CO₂R¹, —SO₂N(R¹)₂,—S(O)_(n)R¹, —OCF₃, —CH2SR⁵, R¹⁰ is hydrogen, halogen, C₁-C₈ alkyloptionally substituted with 1 to 4 halogens, C₃-C₇ cycloalkyl, aryl, CH₂aryl, heteroaryl, heterocycle, —COR¹, —CONR¹R², —SO₂R¹, —N(R¹)₂, —NR¹R²,—CH₂NR¹, R², —CONR¹R² —CO₂R¹, —SO₂N(R¹)₂, —S(O)_(n)R¹, —CH2SR⁵, and n is0-4.
 2. A compound of claim 1, structurally represented by Formula II

or pharmaceutically acceptable salts thereof where: X is O, N or S;R^(1′) is hydrogen, C₁-C₈ alkyl (optionally substituted with 1 to 4halogens or C₁-C₄ alkyls), (CHR^(5′))_(n)—C₃-C₇ cycloalkyl,(CHR^(5′))_(n) aryl, (CHR^(5′))_(n) heteroaryl, or(CHR^(5′))_(n)—O(CHR^(5′))_(n)-aryl; R^(2′) is independently R^(1′), orcyclized with the attached nitrogen atom at the R^(1′) position to forma 5 to 6 member carbon ring (optionally one of said carbons is replacedby one of O, S or N); R^(3′) is independently C₁-C₄ alkyl; R^(4′) ishydrogen, halogen, C₁-C₄ alkyl, (CHR^(5′))_(n)—C₃-C₇ cycloalkyl,(CHR^(5′))_(n) aryl, (CHR^(5′))_(n) heteroaryl,(CHR^(5′))_(n)—O(CHR⁵)_(n)-aryl or carbonyl; R^(5′) is hydrogen or C₁-C₄alkyl; R^(6′) is hydrogen, or cyclized with the attached carbon atom atthe R^(5′) position to form a 5 to 6 member carbon ring, or cyclizedwith the attached carbon atom at the R^(7′) position to form a 5 to 6member heterocyclic ring; R^(7′) is hydrogen, C₁-C₈ alkyl (optionallysubstituted with 1 to 4 halogens or C₁-C₄ alkyls), (CHR^(5′))_(n)—C₃-C₇cycloalkyl, (CHR^(5′))_(n) aryl, (CHR^(5′))_(n) heteroaryl,(CHR^(5′))_(n)—O(CHR⁵)_(n)-aryl R^(8′) is hydrogen, halogen, C₁-C₈ alkyl(optionally substituted with 1 to 4 halogens or C₁-C₄ alkyls), C₃-C₇cycloalkyl, aryl, heteroaryl, —O(CHR^(5′))_(n)-aryl, —COR¹, —SO₂R^(1′),—OR¹, —CN, —CF₃, —N(R^(1′))₂, —NHSO₂R^(1′), —NO₂, —CO₂R^(1′),—SO₂N(R^(1′))₂, —S(O)_(n)R^(1′), or —OCF₃; and n is 0-4.
 3. The compoundof claim 1, wherein X is nitrogen.
 4. The compound of claim 1 or 3wherein the compound is a para disubstituted benzene.
 5. The compound ofany of claims 1, or 34 wherein R⁶ is cyclized with the attached carbonatom at R₇ to form, including the fused benzene ring, a substitutedtetrahydroisoquinoline ring.
 6. The compound of any of claims 1, or 3-4wherein X is nitrogen, and wherein R⁷ and R⁸ are cyclized to form,together with X, a pyrrolidine ring, and wherein R⁹ is—CH2-N-pyrrolidinyl.
 7. The compound of any of claims 1, or 3-6,selected from the group consisting of: Example Number Structure 1

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or a pharmaceutically acceptable salt or solvate thereof.
 8. A compoundof claim 1 wherein the compound has the structure:

or a pharmaceutically acceptable salt or solvate thereof.
 9. A compoundof claim 1 wherein the compound has the structure:

or a pharmaceutically acceptable salt or solvate thereof.
 10. A compoundof claim 1 wherein the compound has the structure:

or a pharmaceutically acceptable salt or solvate thereof.
 11. A compoundof claim 1 wherein the compound has the structure:

or a pharmaceutically acceptable salt or solvate thereof.
 12. A compoundof claim 1 wherein the compound has the structure:

or a pharmaceutically acceptable salt or solvate thereof.
 13. A compoundof claim 1 wherein the compound has the structure:

or a pharmaceutically acceptable salt or solvate thereof.
 14. Apharmaceutical composition which comprises a compound of any of claims1-14 and a pharmaceutically acceptable carrier.
 15. A method ofselectively increasing histamine levels in cells by contacting the cellswith an antagonist of the histamine H3 receptor, said antagonists beinga compound of any of claims 1-14.
 16. A method of selectively increasinghistamine levels in cells by contacting the cells with an antagonist ofthe histamine H3 receptor, said antagonists being a compound of claim 2.17. A method of selectively increasing histamine levels in cells bycontacting the cells with an antagonist of the histamine H3 receptor,said antagonists being a compound of claim
 7. 18. A method ofselectively increasing histamine levels in cells by contacting the cellswith an antagonist of the histamine H3 receptor, said antagonists beinga compound of claim
 9. 19. A method of selectively increasing histaminelevels in cells by contacting the cells with an antagonist of thehistamine H3 receptor, said antagonists being a compound of claim 11.20. The method of claim 15 wherein the antagonist is characterized byhaving little or no binding affinity for the histamine receptor H4R. 21.A method for treatment or prevention of obesity which comprisesadministering to a subject in need of such treatment or prevention aneffective amount of a compound of any of claims 1-14.
 22. A method fortreatment or prevention of a disorder or disease in which inhibition ofthe histamine H3 receptor has a beneficial effect which comprisesadministering to a subject in need of such treatment or prevention aneffective amount of a compound of any of claims 1-14.
 23. A method fortreatment or prevention of a disorder or disease in which inhibition ofthe histamine H3 receptor has a beneficial effect which comprisesadministering to a subject in need of such treatment or prevention aneffective amount of a compound of claim
 2. 24. A method for treatment orprevention of a disorder or disease in which inhibition of the histamineH3 receptor has a beneficial effect which comprises administering to asubject in need of such treatment or prevention an effective amount of acompound of claim
 7. 25. A method for treatment or prevention of adisorder or disease in which inhibition of the histamine H3 receptor hasa beneficial effect which comprises administering to a subject in needof such treatment or prevention an effective amount of a compound ofclaim
 9. 26. A method for treatment or prevention of a disorder ordisease in which inhibition of the histamine H3 receptor has abeneficial effect which comprises administering to a subject in need ofsuch treatment or prevention an effective amount of a compound of claim11.